Cyclic compounds

ABSTRACT

The present invention provides compounds having a Toll-like receptor 4 (TLR4) signaling inhibitory action useful as preventive and therapeutic drugs of inflammatory disease and/or central nervous system disease or diseases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liver injury, ischemia-reperfusion injury (IRI) and the like. The present invention relates to a compound represented by formula (I) and a salt thereof: 
                         
(wherein, each symbol is explained in greater detail in the specification).

TECHNICAL FIELD

The present invention relates to novel cyclic compounds having aToll-like receptor 4 (TLR4) signal inhibitory action useful aspreventive and therapeutic drugs of autoimmune disease and/orinflammatory disease or diseases such as chemotherapy-induced peripheralneuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liverinjury, ischemia-reperfusion injury (IRI) and the like, and use thereof.

BACKGROUND OF THE INVENTION

TLR4 was initially discovered as a receptor which recognizeslipopolysaccharide of Gram negative bacteria and activates the naturalimmunity system. However, in recent years, it has been elucidated thatnot only does TLR4 activate such natural immunity reactions forpreventing infections, but also recognizes various endogenous ligandsproduced in said various diseases and activates various cells playingcentral roles in the said diseases. Moreover, it has been reported thatexpression of TLR4 is accentuated in lesions of various diseases andthat onset and progression of diseases in disease model animals aremarkedly suppressed in TLR4 knockout mouse and mutant mouse.Accordingly, it is suggested that TLR4 plays an important role inautoimmune disease and/or inflammatory disease, and diseases such ascardiac disease, renal disease, liver disease, central nervous systemdisease, infectious disease, malignant tumor, sepsis, septic shock andthe like.

In addition to such diseases, the relationship to ischemia-reperfusioninjury (ischemia reperfusion injury: IRI) caused by reperfusion of bloodflow to organs and tissues in ischemic condition upon organtransplantation and the like, is also reported. High Mobility Group Box1 (HMGB-1), which is one of TLR4 endogenous ligands, increases intransplanted organ. Moreover, the transplanted organ derived from donorwith genetically impaired TLR4 function shows resistance toIRI-associated dysfunction. From such publicly known knowledge, it issuggested that TLR4 signal due to HMGB-1 plays an important role in IRI(Non-Patent Document 1, Non-Patent Document 2).

As a result, TLR4 signaling inhibitors (may also be called “TLR4inhibitors”) are anticipated to be preventive and therapeutic drugs ofautoimmune disease and/or inflammatory disease or diseases such ascardiac disease, renal disease, liver disease, central nervous systemdisease, infectious disease, malignant tumor, sepsis, septic shock, etc.

In Patent Document 1 the following compound

(wherein, each symbol is described in the description in the saidliterature) is reported as a TLR4 signaling inhibitor.

In Patent Document 2 the following compound

(wherein, each symbol is described in the description in the saidliterature) is reported as a TLR4 signaling inhibitor.

In Patent Documents 3 and 4 the following compound

(wherein, each symbol is described in the description in the saidliterature) is reported as TLR4 signaling inhibitor.

DOCUMENT LIST Patent Document

-   [Patent Document 1] WO 99/46242-   [Patent Document 2] WO 2001/010826-   [Patent Document 3] WO 2007/032362-   [Patent Document 4] JP 2008-260760

Non-Patent Document

-   [Non-Patent Document 1] Liver Transpl. 2008 October, 14(10), 1517-25-   [Non-Patent Document 2] J. Hepatol. 2010 July 53(1), 67-72

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The object of the present invention is to provide a compound havingexcellent TLR4 signaling inhibitory action, which is useful as a drug inthe treatment and prevention autoimmune disease and/or inflammatorydisease, and diseases such as chemotherapy-induced peripheral neuropathy(CIPN), chemotherapy-induced neuropathic pain (CINP), liver injury,ischemia-reperfusion injury (IRI) and the like.

Means of Solving the Problems

These inventors made assiduous investigations in order to achieve asolution to said problem, and as a result, it was discovered that thecompounds represented by the following formula (I) have excellent TLR4signaling inhibitory action. The present invention was completed on thebasis of this discovery.

In other words, the present invention is as follows.

(1) A compound represented by the following formula (I) or a saltthereof (hereinafter, abbreviated to compound (I):

(wherein,Ring A is an optionally substituted 5 or 6 membered ring;Ring B is an optionally substituted benzene ring;R¹ and R² are independently a hydrogen atom or a substituent, or R¹ andR² may bond together to form an optionally substituted ring;W is CH₂, NH or O; andR³ is a substituent).(2) The compound or salt according to the above-mentioned (1), whereinRing A is cyclopentene or cyclohexene.(3) The compound or salt according to the above-mentioned (1), whereinRing B is a benzene ring optionally substituted by 1 to 3 substituent(s)selected from a halogen atom and a C₁₋₆ alkyl group.(4) The compound or salt according to the above-mentioned (1), whereinas to R¹ and R², (1) R¹ and R² are both hydrogen atoms, or (2) one of R¹and R² is a hydrogen atom, and the other is a hydroxy group, or R¹ andR² may bond together to form a 3- to 8-membered monocyclic non-aromaticheterocycle optionally substituted by 1 to 3 C₁₋₆ alkyl group(s)optionally substituted by 1 to 3 substituent(s) selected from a hydroxygroup and a C₁₋₆ alkoxy group.(5) The compound or salt according to the above-mentioned (1), wherein Wis CH₂ or O.(6) The compound or salt according to the above-mentioned (1), whereinR³ is a C₁₋₆ alkoxy group optionally substituted by 1 to 3 C₃₋₁₀cycloalkyl group(s) optionally substituted by 1 to 3 C₁₋₆ alkylgroup(s).(7) The compound or salt according to the above-mentioned (1), whereinRing A is cyclopentene or cyclohexene;Ring B is a benzene ring optionally substituted by 1 to 3 substituent(s)selected from a halogen atom and a C₁₋₆ alkyl group;as to R¹ and R², (1) R¹ and R² are both hydrogen atoms, or (2) one of R¹and R² is a hydrogen atom, and the other is a hydroxy group, or R¹ andR² may bond together to form a 3- to 8-membered monocyclic non-aromaticheterocycle, which is optionally substituted by 1 to 3 C₁₋₆ alkylgroup(s) optionally substituted by 1 to 3 substituent(s) selected from ahydroxy group and a C₁₋₆ alkoxy group;W is CH₂ or O; andR³ is a C₁₋₆ alkoxy group optionally substituted by 1 to 3 C₃₋₁₀cycloalkyl group(s) optionally substituted by 1 to 3 C₁₋₆ alkylgroup(s).(8) Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.(9) Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.(10) Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.(11) A medicament comprising the compound or salt according to theabove-mentioned (1).(12) The medicament according to the above-mentioned (11), which is atoll-like receptor 4 inhibitor.(13) The medicament according to the above-mentioned (11), which is anagent for the prophylaxis or treatment of autoimmune disease and/orinflammatory disease.(14) The medicament according to the above-mentioned (11), which is anagent for the prophylaxis or treatment of chemotherapy-inducedperipheral neuropathy (CIPN), chemotherapy-induced neuropathic pain(CINP), liver injury and/or ischemia-reperfusion injury (IRI).(15) The compound or salt according to the above-mentioned (1) for usein the prophylaxis or treatment of autoimmune disease and/orinflammatory disease.(16) The compound or salt according to the above-mentioned (1) for usein the prophylaxis or treatment of chemotherapy-induced peripheralneuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liverinjury and/or ischemia-reperfusion injury (IRI).(17) A method of inhibiting toll-like receptor 4 in a mammal, whichcomprises administering an effective amount of the compound or saltaccording to the above-mentioned (1) to the mammal.(18) A method for the prophylaxis or treatment of autoimmune diseaseand/or inflammatory disease in a mammal, which comprises administeringan effective amount of the compound or salt according to theabove-mentioned (1) to the mammal.(19) A method for the prophylaxis or treatment of chemotherapy-inducedperipheral neuropathy (CIPN), chemotherapy-induced neuropathic pain(CINP), liver injury and/or ischemia-reperfusion injury (IRI) in amammal, which comprises administering an effective amount of thecompound or salt according to the above-mentioned (1) to the mammal.(20) Use of the compound or salt according to the above-mentioned (1)for the production of an agent for the prophylaxis or treatment ofautoimmune disease and/or inflammatory disease.(21) Use of the compound or salt according to the above-mentioned (1)for the production of an agent for the prophylaxis or treatment ofchemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-inducedneuropathic pain (CINP), liver injury and/or ischemia-reperfusion injury(IRI).

Effect of the Invention

The compound of the present invention has TLR4 signaling inhibitoryaction and is useful as a preventive and therapeutic drug of autoimmunedisease and/or inflammatory disease or disease such aschemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-inducedneuropathic pain (CINP), liver injury, ischemia-reperfusion injury(IRI), etc.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in detail.

The definition of each substituent used in this specification will nowbe described in detail. Each substituent has the following definitionsunless otherwise specifically stated to the contrary.

In this specification, for example, as “halogen atom”, fluorine,chlorine, bromine, iodine and the like may be proposed.

In this specification, for example, as “C₁₋₆ alkyl group”, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 1-ethyl propyl, hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl butyland the like may be proposed.

In this specification, for example, as “optionally halogenated C₁₋₆alkyl group”, C₁₋₆ alkyl group which may have 1 to 7, preferably 1 to 5halogen atoms and the like may be proposed. Specific examples comprisemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3, 3, 3-trifluoropropyl,isopropyl, butyl, 4, 4, 4-trifluorobutyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl,hexyl, and 6, 6, 6-trifluoro hexyl.

In this specification, for example, as “C₂₋₆ alkenyl group”, ethenyl,1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and thelike may be proposed.

In this specification, for example, as “C₂₋₆ alkynyl group”, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl and the like may be proposed.In this specification, for example, as “C₃₋₁₀ cycloalkyl group”,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1] heptyl, bicyclo[2.2.2] octyl, bicyclo[3.2.1]octyl, adamantyl and the like may be proposed.

In this specification, for example, as “optionally halogenated C₃₋₁₀cycloalkyl group”, C₃₋₁₀ cycloalkyl group which may have 1 to 7,preferably 1 to 5 halogen atoms and the like may be proposed. Specificexamples comprise cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In this specification, for example, as “C₃₋₁₀ cycloalkenyl group”,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl and the like may be proposed.

In this specification, for example, as “C₆₋₁₄ aryl group”, phenyl,1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and the like maybe proposed.

In this specification, for example, as “C₇₋₁₆ aralkyl group”, benzyl,phenethyl, naphthylmethyl, phenylpropyl and the like may be proposed.

In this specification, for example, as “C₁₋₆ alkoxy group”, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, hexyloxy and the like may be proposed.

In this specification, for example, as “optionally halogenated C₁₋₆alkoxy group”, C₁₋₆ alkoxy group which may have 1 to 7, preferably 1 to5 halogen atoms and the like may be proposed. Specific examples comprisemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In this specification, for example, as “C₃₋₁₀ cycloalkyloxy group”,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, cyclooctyloxy and the like may be proposed.

In this specification, for example, as “C₁₋₆ alkylthio group”,methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like may beproposed.

In this specification, for example, as “optionally halogenated C₁₋₆alkylthio group”, C₁₋₆ alkylthio group which may have 1 to 7, preferably1 to 5 halogen atoms and the like may be proposed.

Specific examples comprise methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio and hexylthio.

In this specification, for example, as “C₁₋₆ alkyl-carbonyl group”,acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl,heptanoyl and the like may be proposed.

In this specification, for example, as “optionally halogenated C₁₋₆alkyl-carbonyl group”, C₁₋₆ alkyl-carbonyl group which may have 1 to 7,preferably 1 to 5 halogen atoms and the like may be proposed. Specificexamples comprise acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In this specification, for example, as “C₁₋₆ alkoxy-carbonyl group”,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the likemay be proposed.

In this specification, for example, as “C₆₋₁₄ aryl-carbonyl group”,benzoyl, 1-naphthoyl, 2-naphthoyl and the like may be proposed.

In this specification, for example, as “C₇₋₁₆ aralkyl-carbonyl group”,phenylacetyl, phenyl propionyl and the like may be proposed.

In this specification, for example, as “5 to 14 membered aromaticheterocyclyl-carbonyl group”, nicotinoyl, isonicotinoyl, thenoyl, furoylmay be proposed.

In this specification, for example, as “3 to 14 membered non-aromaticheterocyclyl-carbonyl group”, morpholinyl carbonyl, piperidinylcarbonyl,pyrrolidinylcarbonyl may be proposed.

In this specification, for example, as “mono- or di-C₁₋₆ alkyl-carbamoylgroup”, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, N-ethyl-N-methylcarbamoyl may be proposed.

In this specification, for example, as “mono- or di-C₇₋₁₆aralkyl-carbamoyl group”, benzylcarbamoyl, phenethylcarbamoyl may beproposed.

In this specification, for example, as “C₁₋₆ alkylsulfonyl group”,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like may beproposed.

In this specification, for example, as “optionally halogenated C₁₋₆alkylsulfonyl group”, C₁₋₆ alkylsulfonyl group which may have 1 to 7,preferably 1 to 5 halogen atoms and the like may be proposed. Specificexamples comprise methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In this specification, for example, as “C₆₋₁₄ arylsulfonyl group”,phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like maybe proposed.

In this specification, for example, as “substituent”, halogen atom,cyano group, nitro group, optionally substituted hydrocarbon group,optionally substituted heterocyclic group, acyl group, optionallysubstituted amino group, optionally substituted carbamoyl group,optionally substituted thiocarbamoyl group, optionally substitutedsulfamoyl group, optionally substituted hydroxy group, optionallysubstituted sulfanyl (SH) group, optionally substituted silyl group andthe like may be proposed.

In this specification, for example as “hydrocarbon group” (including“hydrocarbon group” in “in optionally substituted hydrocarbon group”),C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₃₋₁₀cycloalkyl group, C₃₋₁₀ cycloalkenyl group, C₆₋₁₄ aryl group and C₇₋₁₆aralkyl group may be proposed.

In this specification, for example, as “optionally substitutedhydrocarbon group”, optionally substituted hydrocarbon group selectedfrom the following substituent group A may be proposed.

Substituent Group A

(1) Halogen atom,

(2) Nitro group,

(3) Cyano group,

(4) Oxo group,

(5) Hydroxy group,

(6) Optionally halogenated C₁₋₆ alkoxy group,

(7) C₆₋₁₄ aryloxy group (for example, phenoxy, naphthoxy),

(8) C₇₋₁₆ aralkyloxy group (for example, benzyloxy),

(9) 5 to 14 membered aromatic heterocyclyl-oxy group (for example,pyridyloxy),

(10) 3 to 14 membered non-aromatic heterocyclyl-oxy group (for example,morpholinyloxy, piperidinyloxy),

(11) C₁₋₆ alkyl-carbonyloxy group (for example, acetoxy, propanoyloxy),

(12) C₆₋₁₄ aryl-carbonyloxy group (for example benzoyloxy,1-naphthoyloxy, 2-naphthoyloxy),

(13) C₁₋₆ alkoxy-carbonyloxy group (for example, methoxycarbonyloxy,ethoxycarbonyloxy, propoxy carbonyloxy, butoxycarbonyloxy),

(14) Mono- or di-C₁₋₆ alkyl-carbamoyloxy group (for example,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),

(15) C₆₋₁₄ aryl-carbamoyloxy group (for example, phenylcarbamoyloxy,naphthylcarbamoyloxy),

(16) 5 to 14 membered aromatic heterocyclyl-carbonyloxy group (forexample, nicotinoyloxy),

(17) 3 to 14 membered non-aromatic heterocyclyl-carbonyloxy group (forexample, morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) Optionally halogenated C₁₋₆ alkylsulfonyloxy group (for example,methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) C₆₋₁₄ arylsulfonyloxy group (for example, phenylsulfonyloxy,toluenesulfonyloxy) optionally substituted by C₁₋₆ alkyl group,

(20) Optionally halogenated C₁₋₆ alkylthio group,

(21) 5 to 14 membered aromatic heterocyclic group,

(22) 3 to 14 membered non-aromatic heterocyclic group,

(23) Formyl group,

(24) Carboxy group,

(25) Optionally halogenated C₁₋₆ alkyl-carbonyl group,

(26) C₆₋₁₄ aryl-carbonyl group,

(27) 5 to 14 membered aromatic heterocyclyl-carbonyl group,

(28) 3 to 14 membered non-aromatic heterocyclyl-carbonyl group,

(29) C₁₋₆ alkoxy-carbonyl group,

(30) C₆₋₁₄ aryloxy-carbonyl group (for example phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) C₇₋₁₆ aralkyloxy-carbonyl group (for example benzyloxycarbonyl,phenethyloxycarbonyl),

(32) Carbamoyl group,

(33) Thiocarbamoyl group,

(34) Mono- or di-C₁₋₆ alkyl-carbamoyl group,

(35) C₆₋₁₄ aryl-carbamoyl group (for example, phenylcarbamoyl),

(36) 5 to 14 membered aromatic heterocyclyl-carbamoyl group (forexample, pyridylcarbamoyl, thienylcarbamoyl),

(37) 3 to 14 membered non-aromatic heterocyclyl-carbamoyl group (forexample, morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) Optionally halogenated C₁₋₆ alkylsulfonyl group,

(39) C₆₋₁₄ arylsulfonyl group,

(40) 5 to 14 membered aromatic heterocyclylsulfonyl group (for example,pyridyl sulfonyl, thienyl sulfonyl),

(41) Optionally halogenated C₁₋₆ alkylsulfinyl group,

(42) C₆₋₁₄ arylsulfinyl group (for example phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthyl sulfinyl),

(43) 5 to 14 membered aromatic heterocyclyl-sulfinyl group (for example,pyridyl sulfinyl, thienyl sulfinyl),

(44) Amino group,

(45) Mono- or di-C₁₋₆ alkylamino group (for example methylamino,ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) Mono- or di-C₆₋₁₄ arylamino group (for example, phenylamino),

(47) 5 to 14 membered aromatic heterocyclyl-amino group (for example,pyridylamino),

(48) C₇₋₁₆ aralkylamino group (for example, benzylamino),

(49) Formylamino group,

(50) C₁₋₆ alkyl-carbonylamino group (for example, acetylamino,propanoylamino, butanoylamino),

(51) (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (for exampleN-acetyl-N-methylamino),

(52) C₆₋₁₄ aryl-carbonylamino group (for example, phenyl carbonylamino,naphthyl carbonylamino),

(53) C₁₋₆ alkoxy-carbonylamino group (for example methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),

(54) C₇₋₁₆ aralkyloxy-carbonylamino group (for examplebenzyloxycarbonylamino),

(55) C₁₋₆ alkylsulfonylamino group (for example, methylsulfonylamino,ethylsulfonylamino),

(56) C₆₋₁₄ arylsulfonylamino group (for example, phenylsulfonylamino,toluenesulfonylamino) optionally substituted by C₁₋₆ alkyl group,

(57) Optionally halogenated C₁₋₆ alkyl group,

(58) C₂₋₆ alkenyl group,

(59) C₂₋₆ alkynyl group,

(60) C₃₋₁₀ cycloalkyl group,

(61) C₃₋₁₀ cycloalkenyl group, and,

(62) C₆₋₁₄ aryl group.

For example, in “optionally substituted hydrocarbon group”, said numberof substituents is 1 to 5, preferably 1 to 3. When the number ofsubstituents is 2 or more, each substituent may be the same ordifferent.

In this specification, as “heterocyclic group” (including “heterocyclicgroup” in “optionally substituted heterocyclic group”), for example (i)aromatic heterocyclic group, (ii) non-aromatic heterocyclic group and(iii) 7-10 membered bridged heterocyclic group, each containingrespectively 1 to 4 heteroatoms selected from oxygen, sulfur andnitrogen atoms in addition to the carbon atom content as ring atoms, maybe proposed.

In this specification, as “aromatic heterocyclic group” (including “5-14membered aromatic heterocyclic group”, 5 to 14 membered (preferably 5 to10 membered) aromatic heterocyclic group containing 1 to 4 heteroatomsselected from nitrogen atom, sulfur atom and oxygen atom in addition tothe carbon atom content as ring atoms, may be proposed.

As ideal examples of said “aromatic heterocyclic group”, 5 to 6 memberedmonocyclic aromatic heterocyclic groups such as thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl etc.; 8 to 14membered condensed polycyclic (preferably bicyclic or tricyclic)aromatic heterocyclic group such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2, 3-b]thienyl, phenoxathienyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalidinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, etc. may be proposed.

In this specification, for example, as “non-aromatic heterocyclic group”(including “3 to 14 membered non-aromatic heterocyclic group”), 3 to 14membered (preferably 4 to 10 membered) non-aromatic heterocyclic group,containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atomand oxygen atom in addition to the carbon atom content as ring atoms,may be proposed.

As ideal example of said “non-aromatic heterocyclic group”, 3 to 8membered monocyclic non-aromatic heterocyclic group such as aziridinyl,oxiranyl, thiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl,imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl,thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl,dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl,tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl,diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, etc.;

9 to 14 membered condensed polycyclic (preferably bicyclic or tricyclic)non-aromatic heterocyclic group such as dihydrobenzofuranyl,dihydrobenzoimidazolyl, dihydrobenzooxazolyl, dihydrobenzothiazolyl,dihydrobenzoisothiazolyl, dihydronaphthop, [2, 3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl,isoindolinyl, tetrahydrothieno[2, 3-c]pyridinyl,tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl,tetrahydrophenanthridinyl, hexahydrophenothiazinyl,hexahydrophenoxazinyl, tetrahydrophthalidinyl, tetrahydronaphthyridinyl,tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl,tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl,tetrahydrothioxanethenyl, octahydroisoquinolyl, etc. may be proposed.

In this specification, as ideal example of “7 to 10 membered bridgedheterocyclic group”, quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl maybe proposed.

In this specification, as “nitrogen-containing heterocyclic group”,those groups among “heterocyclic groups” that contain at least onenitrogen atom as ring atom content may be proposed.

In this specification, for example, as “optionally substitutedheterocyclic group”, heterocyclic groups optionally substituted bysubstituent(s) selected from said substituent group A may be proposed.

The number of substituents in “optionally substituted heterocyclicgroup” is for example 1 to 3. When the number of substituents is 2 ormore, each substituent may be the same or different.

In this specification, as “acyl group”, for example, formyl group,carboxy group, carbamoyl group, thiocarbamoyl group, sulfino group,sulfo group, sulfamoyl group and phosphono group, each respectivelyoptionally substituted by “1 or 2 substituents selected from C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenylgroup, C₆₋₁₄ aryl group, C₇₋₁₆ aralkyl group, 5 to 14 membered aromaticheterocyclic group and 3 to 14 membered non-aromatic heterocyclic group,which may each further have 1 to 3 substituent(s) selected from halogenatoms, optionally halogenated C₁₋₆ alkoxy group, hydroxy group, nitrogroup, cyano group, amino group and carbamoyl group”, may be proposed.

Moreover, as “acyl group”, hydrocarbon-sulfonyl group,heterocyclyl-sulfonyl group, hydrocarbon-sulfinyl group,heterocyclyl-sulfinyl group may also be proposed.

Wherein, as hydrocarbon-sulfonyl group, a sulfonyl group bonded with ahydrocarbon group; as heterocyclyl-sulfonyl group, a sulfonyl groupbonded with a heterocyclic group; as hydrocarbon-sulfinyl group, asulfinyl group bonded with a hydrocarbon group; as heterocyclyl-sulfinylgroup, a sulfinyl group bonded with a heterocyclic group arerespectively denoted.

Ideal examples of “acyl group” include formyl group, carboxy group, C₁₋₆alkyl-carbonyl group, C₂₋₆ alkenyl-carbonyl group (for example,crotonoyl), C₃₋₁₀ cycloalkyl-carbonyl group (for examplecyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), C₃₋₁₀ cycloalkenyl-carbonyl group (for example2-cyclohexenecarbonyl), C₆₋₁₄ aryl-carbonyl group, C₇₋₁₆aralkyl-carbonyl group, 5 to 14 membered aromatic heterocyclyl-carbonylgroup, 3 to 14 membered non-aromatic heterocyclyl-carbonyl group, C₁₋₆alkoxy-carbonyl group, C₆₋₁₄ aryloxy-carbonyl group (for example,phenyloxycarbonyl, naphthyloxycarbonyl), C₇₋₁₆ aralkyloxy-carbonyl group(for example, benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group,mono- or di-C₁₋₆ alkyl-carbamoyl group, mono- or di-C₂₋₆alkenyl-carbamoyl group (for example, diallylcarbamoyl), mono- ordi-C₃₋₁₀ cycloalkyl-carbamoyl group (for example, cyclopropylcarbamoyl),mono- or di-C₆₋₁₄ aryl-carbamoyl group (for example, phenylcarbamoyl),mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, 5 to 14 membered aromaticheterocyclyl-carbamoyl group (for example, pyridylcarbamoyl),thiocarbamoyl group, mono- or di-C₁₋₆ alkyl-thiocarbamoyl group (forexample methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- ordi-C₂₋₆ alkenyl-thiocarbamoyl group (for example, diallylthiocarbamoyl),mono- or di-C₃₋₁₀ cycloalkyl-thiocarbamoyl group (for example,cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C₆₋₁₄aryl-thiocarbamoyl group (for example, phenylthiocarbamoyl), mono- ordi-C₇₋₁₆ aralkyl-thiocarbamoyl group (for example, benzylthiocarbamoyl,phenethylthiocarbamoyl), 5 to 14 membered aromaticheterocyclyl-thiocarbamoyl group (for example, pyridylthiocarbamoyl),sulfino group, C₁₋₆ alkylsulfinyl group (for example, methylsulfinyl,ethyl sulfinyl), sulfo group, C₁₋₆ alkylsulfonyl group, C₆₋₁₄ arylsulfonyl group, phosphono group, mono- or di-C₁₋₆ alkyl phosphono group(for example, dimethylphosphone, diethylphosphone, diisopropylphosphoneand dibutylphosphono) may be proposed.

In this specification, for example, as “optionally substituted aminogroup”, an amino group which may have “1 or 2 substituents selected fromC₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkyl group, C₆₋₁₄ arylgroup, C₇₋₁₆ aralkyl group, C₁₋₆ alkyl-carbonyl group, C₆₋₁₄aryl-carbonyl group, C₇₋₁₆ aralkyl-carbonyl group, 5 to 14 memberedaromatic heterocyclyl-carbonyl group, 3 to 14 membered non-aromaticheterocyclyl-carbonyl group, C₁₋₆ alkoxy-carbonyl group, 5 to 14membered aromatic heterocyclic groups, carbamoyl group, mono- or di-C₁₋₆alkyl-carbamoyl group, mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, C₁₋₆alkylsulfonyl group and C₆₋₁₄ aryl sulfonyl group, which substituentsmay each respectively be substituted by 1-3 substituents selected fromsubstituent group A” may be proposed.

As ideal examples of an optionally substituted amino group, an aminogroup, mono- or di-(optionally halogenated C₁₋₆ alkyl) amino group (forexample, methylamino, trifluoromethylamino, dimethylamino, ethylamino,diethylamino, propylamino, dibutylamino), mono- or di-C₂₋₆ alkenylaminogroup (for example, diallylamino), mono- or di-C₃₋₁₀ cycloalkylaminogroup (for example, cyclopropylamino, cyclohexylamino), mono- ordi-C₆₋₁₄ arylamino group (for example, phenylamino), mono- or di-C₇₋₁₆aralkylamino group (for example, benzylamino, dibenzylamino), mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (for example,acetylamino, propionylamino), mono- or di-C₆₋₁₄ aryl-carbonylamino group(for example, benzoylamino), mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (for example, benzylcarbonylamino), mono- or di-5 to 14 memberedaromatic heterocyclyl-carbonylamino group (for example, nicotinoylamino,isonicotinoylamino), mono- or di-3 to 14 membered non-aromaticheterocyclyl-carbonylamino group (for example, piperidinylcarbonylamino), mono- or di-C₁₋₆ alkoxy-carbonylamino group (for exampletert-butoxycarbonylamino), 5 to 14 membered aromatic heterocyclyl-aminogroup (for example, pyridylamino), carbamoylamino group, (mono- ordi-C₁₋₆ alkyl-carbamoyl)amino group (for example, methylcarbamoylamino),(mono- or di-C₇₋₁₆ aralkyl-carbamoyl)amino group (for example,benzylcarbamoylamino), C₁₋₆ alkylsulfonylamino group (for example,methylsulfonylamino, ethylsulfonylamino), C₆₋₁₄ arylsulfonylamino group(for example, phenylsulfonylamino), (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (for example N-acetyl-N-methylamino), (C₁₋₆ alkyl) (C₆₋₁₄aryl-carbonyl) amino group (for example N-benzoyl-N-methylamino) may beproposed.

In this specification, as “optionally substituted carbamoyl group”, forexample, a carbamoyl group optionally substituted by “1 or 2substituent(s) selected from C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₃₋₁₀cycloalkyl group, C₆₋₁₄ aryl group, C₇₋₁₆ aralkyl group, C₁₋₆alkyl-carbonyl group, C₆₋₁₄ aryl-carbonyl group, C₇₋₁₆ aralkyl-carbonylgroup, 5 to 14 membered aromatic heterocyclyl-carbonyl group, 3 to 14membered non-aromatic heterocyclyl-carbonyl group, C₁₋₆ alkoxy-carbonylgroup, 5 to 14 membered aromatic heterocyclic group, carbamoyl group,mono- or di-C₁₋₆ alkyl-carbamoyl group and mono- or di-C₇₋₁₆aralkyl-carbamoyl group, each of which substituents may be optionallysubstituted by 1 to 3 substituent(s) selected from substituent group A”may be proposed.

As ideal examples of optionally substituted carbamoyl group, carbamoylgroup, mono- or di-C₁₋₆ alkyl-carbamoyl group, mono- or di-C₂₋₆alkenyl-carbamoyl group (for example, diallylcarbamoyl), mono- ordi-C₃₋₁₀ cycloalkyl-carbamoyl group (for example, cyclopropylcarbamoyl,cyclohexylcarbamoyl), mono- or di-C₆₋₁₄ aryl-carbamoyl group (forexample, phenylcarbamoyl), mono- or di-C₇₋₁₆ aralkyl-carbamoyl group,mono- or di-C₁₋₆ alkyl-carbonyl-carbamoyl group (for example,acetylcarbamoyl, propionylcarbamoyl), mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (for example, benzoylcarbamoyl), and 5 to14 membered aromatic heterocyclyl-carbamoyl group (for example,pyridylcarbamoyl) may be proposed.

In this specification, as “optionally substituted thiocarbamoyl group”,for example, a thiocarbamoyl group which may have “1 or 2 substituent(s)selected from C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkylgroup, C₆₋₁₄ aryl group, C₇₋₁₆ aralkyl group, C₁₋₆ alkyl-carbonyl group,C₆₋₁₄ aryl-carbonyl group, C₇₋₁₆ aralkyl-carbonyl group, 5 to 14membered aromatic heterocyclyl-carbonyl group, 3 to 14 memberednon-aromatic heterocyclyl-carbonyl groups, C₁₋₆ alkoxy-carbonyl group, 5to 14 membered aromatic heterocyclic group, carbamoyl group, mono- ordi-C₁₋₆ alkyl-carbamoyl group and mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup”, wherein each of such substituents may respectively have 1 to 3substituent(s) selected from substituent group A” and may be proposed.

Ideal examples of optionally substituted thiocarbamoyl group comprise athiocarbamoyl group, mono- or di-C₁₋₆ alkyl-thiocarbamoyl group (forexample, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl,diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C₂₋₆alkenyl-thiocarbamoyl group (for example, diallylthiocarbamoyl), mono-or di-C₃₋₁₀ cycloalkyl-thiocarbamoyl group (for example,cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C₆₋₁₄aryl-thiocarbamoyl group (for example, phenylthiocarbamoyl), mono- ordi-C₇₋₁₆ aralkyl-thiocarbamoyl group (for example, benzylthiocarbamoyl,phenethylthiocarbamoyl), mono- or di-C₁₋₆ alkyl-carbonyl-thiocarbamoylgroup (for example, acetylthiocarbamoyl, propionylthiocarbamoyl), mono-or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoyl group (for example,benzoylthiocarbamoyl), and 5 to 14 membered aromaticheterocyclyl-thiocarbamoyl group (for example, pyridylthiocarbamoyl).

In this specification, as “optionally substituted sulfamoyl group”, asulfamoyl group which may have 1 or 2 substituent(s) selected from C₁₋₆alkyl group, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkyl group, C₆₋₁₄ arylgroup, C₇₋₁₆ aralkyl group, C₁₋₆ alkyl-carbonyl group, C₆₋₁₄aryl-carbonyl group, C₇₋₁₆ aralkyl-carbonyl group, 5 to 14 memberedaromatic heterocyclyl-carbonyl group, 3 to 14 membered non-aromaticheterocyclyl-carbonyl group, C₁₋₆ alkoxy-carbonyl group, 5 to 14membered aromatic heterocyclic group, carbamoyl group, mono- or di-C₁₋₆alkyl-carbamoyl group and mono- or di-C₇₋₁₆ aralkyl-carbamoyl group,wherein each of such substituents may respectively have 1 to 3substituent(s) selected from substituent group A” may be proposed.

Ideal examples of optionally substituted sulfamoyl group comprise asulfamoyl group, mono- or di-C₁₋₆ alkyl-sulfamoyl group (for example,methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl,N-ethyl-N-methylsulfamoyl), mono- or di-C₂₋₆ alkenyl-sulfamoyl group(for example, diallylsulfamoyl), mono- or di-C₃₋₁₀ cycloalkyl-sulfamoylgroup (for example, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- ordi-C₆₋₁₄ aryl-sulfamoyl group (for example, phenylsulfamoyl), mono- ordi-C₇₋₁₆ aralkyl-sulfamoyl group (for example, benzylsulfamoyl,phenethylsulfamoyl), mono- or di-C₁₋₆ alkyl-carbonyl-sulfamoyl group(for example, acetylsulfamoyl, propionylsulfamoyl), mono- or di-C₆₋₁₄aryl-carbonyl-sulfamoyl group (for example, benzoylsulfamoyl) and 5 to14 membered aromatic heterocyclyl-sulfamoyl group (for example,pyridylsulfamoyl).

In this specification, as “optionally substituted hydroxy group”, anhydroxy group which may have “a substituent selected from C₁₋₆ alkylgroup, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkyl group, C₆₋₁₄ aryl group,C₇₋₁₆ aralkyl group, C₁₋₆ alkyl-carbonyl group, C₆₋₁₄ aryl-carbonylgroup, C₇₋₁₆ aralkyl-carbonyl group, 5 to 14 membered aromaticheterocyclyl-carbonyl group, 3 to 14 membered non-aromaticheterocyclyl-carbonyl group, C₁₋₆ alkoxy-carbonyl group, 5 to 14membered aromatic heterocyclic group, carbamoyl group, mono- or di-C₁₋₆alkyl-carbamoyl group, mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, C₁₋₆alkylsulfonyl group and C₆₋₄ aryl sulfonyl group, wherein each of suchsubstituent may respectively have 1 to 3 substituent(s) selected fromsubstituent group A” may be proposed.

Ideal examples of optionally substituted hydroxy group comprise ahydroxy group, C₁₋₆ alkoxy group, C₂₋₆ alkenyloxy group (for example,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C₃₋₁₀cycloalkyloxy group (for example, cyclohexyloxy), C₆₋₁₄ aryloxy group(for example, phenoxy, naphthyloxy), C₇₋₁₆ aralkyloxy group (forexample, benzyloxy, phenethyloxy), C₁₋₆ alkyl-carbonyloxy group (forexample, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,pivaloyloxy), C₆₋₁₄ aryl-carbonyloxy group (for example, benzoyloxy),C₇₋₁₆ aralkyl-carbonyloxy group (for example, benzylcarbonyloxy), 5 to14 membered aromatic heterocyclyl-carbonyloxy group (for example,nicotinoyloxy), 3 to 14 membered non-aromatic heterocyclyl-carbonyloxygroup (for example, piperidinylcarbonyloxy), C₁₋₆ alkoxy-carbonyloxygroup (for example tert-butoxycarbonyloxy). 5 to 14 membered aromaticheterocyclyl-oxy group (for example, pyridyloxy), carbamoyloxy group,C₁₋₆ alkyl-carbamoyloxy group (for example, methylcarbamoyloxy), C₇₋₁₆aralkyl-carbamoyloxy group (for example, benzylcarbamoyloxy), C₁₋₆alkylsulfonyloxy group (for example, methylsulfonyloxy,ethylsulfonyloxy) and C₆₋₁₄ arylsulfonyloxy group (for example,phenylsulfonyloxy).

In this specification, as “optionally substituted sulfanyl group”, forexample, sulfanyl group which may have “a substituent selected from C₁₋₆alkyl group, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkyl group, C₆₋₁₄ arylgroup, C₇₋₁₆ aralkyl group, C₁₋₆ alkyl-carbonyl group, C₆₋₁₄aryl-carbonyl group and 5 to 14 membered aromatic heterocyclic group,wherein each of such substituents may respectively have 1 to 3substituents selected from substituent group A” and halogenated sulfanylgroup may be proposed.

Ideal examples of optionally substituted sulfanyl group comprise asulfanyl (—SH) group, C₁₋₆ alkylthio group, C₂₋₆ alkenylthio group (forexample allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C₃₋₁₀cycloalkylthio group (for example, cyclohexylthio), C₆₋₁₄ arylthio group(for example, phenylthio, naphthylthio), C₇₋₁₆ aralkylthio group (forexample, benzylthio, phenethylthio), C₁₋₆ alkyl-carbonylthio group (forexample, acetylthio, propionylthio, butyrylthio, isobutyrylthio,pivaloylthio), C₆₋₁₄ aryl-carbonylthio group (for example, benzoylthio),5 to 14 membered aromatic heterocyclyl-thio group (for example,pyridylthio) and halogenated thio group (for example, pentafluorothio).

In this specification, as “optionally substituted silyl group”, forexample, a silyl group which may have “1 to 3 substituent(s) selectedfrom C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₃₋₁₀ cycloalkyl group, C₆₋₁₄aryl group and C₇₋₁₆ aralkyl group, which respectively may have 1 to 3substituent(s) selected from substituent group A” may be proposed.

As ideal examples of optionally substituted silyl group, a tri-C₁₋₆alkyl silyl group (for example trimethylsilyl andtert-butyl(dimethyl)silyl) may be proposed.

In this specification, as “C₁₋₆ alkylene group”, for example, —CH₂—,—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH(CH₃)—, —(CCH₃)₂—,—CH(C₂H₅)—, —CH(C₃H₇)—, —CH(CH(CH₃)₂)—, —(CH(CH₃))₂—, —CH₂—CH(CH₃)—,—CH(CH₃)—CH₂—, —CH₂—CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—CH₂—CH₂— may be proposed.

In this specification, as “C₂₋₆ alkenylene group”, for example, —CH═CH—,—CH₂—CH═CH—, —CH═CH—CH₂—, —C(CH₃)₂—CH═CH—, —CH═CH—C(CH₃)₂—,—CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—, —CH═CH—CH═CH—,—CH═CH—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH═CH— may be proposed.

In this specification, as “C₂₋₆ alkynylene group”, for example, —C≡C—,—CH₂—C≡C—, —C≡C—CH₂—, —(CCH₃)₂—C≡C—, —C≡C—(CH₃)₂—, —CH₂—C≡C—CH₂—,—CH₂—CH₂—C≡C—, —C≡C—CH₂—CH₂—, —C≡C—C≡C—, —C≡C—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—C≡C— may be proposed.

In this specification, as “hydrocarbon ring”, for example, C₆₋₁₄aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane and C₃₋₁₀ cycloalkene maybe proposed.

In this specification, as “C₆₋₁₄ aromatic hydrocarbon ring”, forexample, benzene and naphthalene may be proposed.

In this specification, as “C₃₋₁₀ cycloalkane”, for example,cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane andcyclooctane may be proposed.

In this specification, as “C₃₋₁₀ cycloalkene”, for example,cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene andcyclooctene may be proposed.

In this specification, as “heterocycle”, for example, aromaticheterocycles and non-aromatic heterocycles respectively containing 1 to4 heteroatom(s) selected from nitrogen atom, sulfur atom and oxygen atomin addition to the carbon atom content as ring atoms may be proposed.

In this specification, as “aromatic heterocycle”, for example 5 to 14membered (preferably 5 to 10 membered) aromatic heterocycles containing1 to 4 heteroatom(s) selected from nitrogen atom, sulfur atom and oxygenatom in addition to the carbon atom content as ring atoms may beproposed. Ideal examples of said “aromatic heterocycle” comprise 5 to 6membered monocyclic aromatic heterocycles such as thiophene, furan,pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine, etc.;

and 8 to 14 membered condensed polycyclic (preferably bi- or tri-cyclic)aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole,benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole,benzotriazole, imidazopyridine, thienopyridine, furopyridine,pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine,imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine,pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine,thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine,isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, carbazole, β-carboline, phenanthridine,acridine, phenazine, phenothiazine, phenoxazine, etc. may be proposed.

In this specification, as “non-aromatic heterocycle”, for example, 3 to14 membered (preferably 4 to 10 membered) non-aromatic heterocyclescontaining 1 to 4 heteroatom(s) selected from nitrogen atom, sulfur atomand oxygen atom in addition to the carbon atom content as ring atoms maybe proposed. As ideal examples of said “non-aromatic heterocycle”, 3 to8 membered monocyclic non-aromatic heterocycles such as aziridine,oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene,tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine,oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline,thiazolidine, tetrahydroisothiazole, tetrahydrooxazole,tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine,dihydropyridine, dihydrothiopyran, tetrahydropyrimidine,tetrahydropyridazine, dihydropyran, tetrahydropyran,tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, diazepane,azepine, azocane, diazocane, oxepane, etc., and,

9 to 14 membered condensed polycyclic (preferably bi- or tri-cyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzoimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline,isoindoline, tetrahydrothieno[2, 3-c]pyridine, tetrahydrobenzoazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbozole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline, etc. may be proposed.

In this specification, as “nitrogen-containing heterocycle”, among“heterocycle”, those containing at least 1 nitrogen atom as ring atomsmay be proposed.

In this specification, as represented in the following formulae, when anon-aromatic ring Q condensed with an aromatic ring Q′ is present, thenon-aromatic ring Q forms a ring in which the bond C¹C² is a doublebond.

For example, when said condensed ring QQ′ is an indane ring, a depictionis used whereby the non-aromatic ring Q is cyclopentene ring, and thearomatic ring Q′ is benzene.

The definition of each symbol in formula (I) will now be described indetail.

Ring A is an optionally substituted 5 or 6 membered ring.

As “5 or 6 membered ring” of “optionally further substituted 5 or 6membered ring” represented by Ring A, a benzene ring, C₅₋₆ cycloalkene,5 or 6 membered monocyclic aromatic heterocycle and 5 to 6 memberedmonocyclic non-aromatic heterocycle may be proposed.

As said C₅₋₆ cycloalkene, a 5 or 6 membered cycloalkene among said“C₃₋₁₀ cycloalkene” may be proposed.

As far as said 5 to 6 membered monocyclic aromatic heterocycle isconcerned, 5 to 6 membered monocycle of said “aromatic heterocycle” maybe proposed.

As far as said 5-6 membered monocyclic non-aromatic heterocycle isconcerned, 5 to 6 membered monocycle of said “non-aromatic heterocycle”may be proposed.

The “5 or 6 membered ring” of “optionally further substituted 5 or 6membered ring” represented by Ring A may be further substituted bysubstituent selected from, for example, said substituent group A,wherein the number of substituents is, for example, 1 to 3. When thenumber of substituents is 2 or more, each substituent may be the same ordifferent.

Ring A is preferably optionally further substituted C₅₋₆ cycloalkene(for example, cyclopentene, cyclohexene).

Ring A is more preferably C₅₋₆ cycloalkene (for example cyclopentene,cyclohexene).

Ring A is still more preferably cyclopentene or cyclohexene.

Ring A is particularly preferably cyclopentene.

Ring B is an optionally substituted benzene ring.

The “benzene ring” of “optionally substituted benzene ring” representedby Ring B, for example, may be substituted by substituent orsubstituents selected from said substituent group A, wherein the numberof substituents is for example 1 to 3. When the number of substituentsis 2 or more, each substituent may be the same or different.

Ring B is preferably a benzene ring optionally substituted by 1 to 3substituent(s) selected from (1) a halogen atom (for example, fluorineatom, chlorine atom, bromine atom), and, (2) a C₁₋₆ alkyl group (forexample, methyl).

Ring B is more preferably a benzene ring optionally substituted by 1 to3 halogen atom(s) (for example fluorine atom, chlorine atom).

R¹ and R² are independently a hydrogen atom or a substituent, or R¹ andR² may bond together to form an optionally substituted ring.

As the “ring” of “optionally substituted ring” formed by R¹ and R²bonding together, non-aromatic hydrocarbon ring (C₃₋₁₀ cycloalkane,C₃₋₁₀ cycloalkene) and non-aromatic heterocycle may be proposed.

The “ring” of “optionally substituted ring” formed by R¹ and R² bondingtogether, for example, may be substituted by substituent or substituentsselected from said substituent group A, wherein the number ofsubstituents is for example 1 to 3. When the number of substituents is 2or more, each substituent may be the same or different. Moreover, saidsubstituent group A may also be substituted by substituent orsubstituents selected from substituent group A, wherein the number ofsubstituents is for example 1 to 3. When the number of substituents is 2or more, each substituent may be the same or different.

The “ring” of “optionally substituted ring” formed by R¹ and R² bondingtogether is preferably a 3 to 14 membered (preferably 4 to 10 membered)non-aromatic heterocycle, more preferably a 3 to 8 membered monocyclicnon-aromatic heterocycle (for example, dioxolane).

R¹ and R² are preferably independently a hydrogen atom or an optionallysubstituted hydroxy group or R¹ and R² may bond together to form anoptionally substituted 3-14 membered (preferably 4-10 membered)non-aromatic heterocycle, preferably a 3-8 membered monocyclicnon-aromatic heterocycle (for example, dioxolane).

R¹ and R² are more preferably independently, a hydrogen atom or ahydroxy group (preferably, both are hydrogen atoms, or the one is ahydrogen atom and the other is a hydroxy group) or R¹ and R² may bondtogether to form a 3 to 14 membered (preferably 4 to 10 membered)non-aromatic heterocycle, preferably a 3 to 8 membered monocyclicnon-aromatic heterocycle (for example, dioxolane), which is optionallysubstituted by 1 to 3 C₁₋₆ alkyl group(s) (for example, methyl),optionally substituted by 1 to 3 substituent(s) selected from a hydroxygroup and a C₁₋₆ alkoxy group (for example, methoxy).

Still more preferably, (1) R¹ and R² are both hydrogen atoms, or (2) oneof R¹ and R² is a hydrogen atom, and the other is a hydroxy group, or R¹and R² may bond together to form a 3 to 8 membered monocyclicnon-aromatic heterocycle (for example, dioxolane), which is optionallysubstituted by 1 to 3 C₁₋₆ alkyl group(s) (for example, methyl),optionally substituted by 1 to 3 substituent(s) selected from a hydroxygroup and a C₁₋₆ alkoxy group (for example, methoxy).

Particularly preferably, R¹ and R² may bond together to form a 3 to 14membered (preferably 4 to 10 membered) non-aromatic heterocycle(preferably 3 to 8 membered monocyclic non-aromatic heterocycle (forexample, dioxolane)), which is optionally substituted by 1 to 3 C₁₋₆alkyl group(s) (for example, methyl), optionally substituted by 1 to 3substituent(s) selected from a hydroxy group and a C₁₋₆ alkoxy group(for example, methoxy).

W is CH₂, NH or O.

W is preferably CH₂ or O.

W is more preferably CH₂.

R³ is a substituent.

R³ is preferably an optionally substituted hydroxy group. Substituent(substituent group A) on the optionally substituted hydroxy group mayalso be substituted by substituent selected from substituent group A,wherein the number of substituents is, for example, 1 to 3. When thenumber of substituents is 2 or more, each substituent may be the same ordifferent.

R³ is more preferably an optionally substituted C₁₋₆ alkoxy group (forexample, methoxy, ethoxy).

R³ is further more preferably a C₁₋₆ alkoxy group (for example, methoxy,ethoxy) optionally substituted by 1 to 3 C₃₋₁₀ cycloalkyl group(s) (forexample, cyclopropyl) optionally substituted by 1 to 3 C₁₋₆ alkylgroup(s) (for example, methyl).

R³ is still more preferably a C₁₋₆ alkoxy group (for example, ethoxy).

The following compounds may be proposed as ideal compounds (I).

Compound A

Compound (I),

wherein,

Ring A is C₅₋₆ cycloalkene (for example, cyclopentene, cyclohexene)which may be further substituted,

Ring B is optionally substituted benzene ring,

R¹ and R² are independently hydrogen atom or optionally substitutedhydroxy group, or R¹ and R² may bond together to form an optionallysubstituted 3 to 14 membered (preferably 4 to 10 membered) non-aromaticheterocycle, preferably a 3 to 8 membered monocyclic non-aromaticheterocycle (for example, dioxolane),W is CH₂ or O, and,R³ is an optionally substituted C₁₋₆ alkoxy group (for example, methoxy,ethoxy).Compound B

Compound (I),

wherein,

Ring A is C₅₋₆ cycloalkene (for example cyclopentene, cyclohexene),

Ring B is a benzene ring optionally substituted by 1 to 3 substituent(s)selected from

(1) a halogen atom (for example, fluorine atom, chlorine atom, bromineatom), and,

(2) a C₁₋₆ alkyl group (for example, methyl),

R¹ and R² are independently a hydrogen atom or a hydroxy group(preferably, both are hydrogen atom or the one is a hydrogen atom andthe other is a hydroxy group) or R¹ and R² may bond together to form a3-14 membered (preferably 4-10 members) non-aromatic heterocycle(preferably 3-8 membered monocyclic non-aromatic heterocycle (forexample, dioxolane)) optionally substituted by 1 to 3 C₁₋₆ alkylgroup(s) (for example, methyl), optionally substituted by 1 to 3substituent(s) selected from a hydroxy group and a C₁₋₆ alkoxy group(for example, methoxy),W is CH₂ or O, and,R³ is a C₁₋₆ alkoxy group (for example, methoxy, ethoxy) optionallysubstituted by 1 to 3 C₃₋₁₀ cycloalkyl group(s) (for example,cyclopropyl) optionally substituted by 1 to 3 C₁₋₆ alkyl group(s) (forexample, methyl).Compound C

Compound (I),

wherein,

Ring A is cyclopentene or cyclohexene,

Ring B is a benzene ring optionally substituted by 1 to 3 substituent(s)selected from

(1) a halogen atom (for example, fluorine atom, chlorine atom, bromineatom), and,

(2) a C₁₋₆ alkyl group (for example, methyl),

As to R¹ and R², (1) R¹ and R² are both hydrogen atoms, or (2) one of R¹and R² is a hydrogen atom, and the other is a hydroxy group, or R¹ andR² may bond together to form a 3 to 8 membered monocyclic non-aromaticheterocycle (for example, dioxolane), which is optionally substituted by1 to 3 C₁₋₆ alkyl group(s) (for example, methyl), optionally substitutedby 1 to 3 substituent(s) selected from a hydroxy group and a C₁₋₆ alkoxygroup (for example, methoxy),W is CH₂ or O, and,R³ is a C₁₋₆ alkoxy group (for example, methoxy, ethoxy) optionallysubstituted by 1 to 3 C₃₋₁₀ cycloalkyl group(s) (for example,cyclopropyl) optionally substituted by 1 to 3 C₁₋₆ alkyl group(s) (forexample, methyl).Compound D

Compound (I), wherein,

Ring A is C₅₋₆ cycloalkene (for example, cyclopentene, cyclohexene),

Ring B is a benzene ring optionally substituted by 1 to 3 halogenatom(s) (for example fluorine atom, chlorine atom),

R¹ and R² may bond together to form a 3 to 14 membered (preferably 4 to10 membered) non-aromatic heterocycle (preferably 3 to 8 memberedmonocyclic non-aromatic heterocycle (for example, dioxolane)),optionally substituted by 1 to 3 C₁₋₆ alkyl group(s) (for example,methyl) optionally substituted by 1 to 3 substituent(s) selected from ahydroxy group and a C₁₋₆ alkoxy group (for example, methoxy),W is CH₂, and,R³ is a C₁₋₆ alkoxy group (for example, ethoxy).

The compounds of Example 1-21 may be proposed as specific examples ofsaid compound (I).

Among them, ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(Example 6), ethyl(2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(Example 14), and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(Example 21) are preferable.

When compound (I) is a salt, as such salts, for example, metal salts,ammonium salts, salts with organic bases, salts with inorganic acids,salts with organic acids, salts with basic or acidic amino acids, etc.,may be proposed. Ideal examples of metal salts include alkali metalsalts such as sodium salts, potassium salts, etc., alkaline earth metalsalts such as calcium salts, magnesium salts, barium salts, etc.,aluminum salts, etc. Ideal examples of salts with organic base includesalts with, for example, trimethylamine, triethylamine, pyridine,picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.Ideal examples of salts with inorganic acids, include salts with, forexample, hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc. Ideal examples of salts with organic acids,include salts with, for example, formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.Ideal examples of salts with basic amino acids, include salts with, forexample, arginine, lysine, ornithine, etc., and as ideal examples ofsalts with acidic amino acids, salts with, for example, aspartic acid,glutamic acid, etc. may be proposed.

Among these, pharmacologically permitted salts are preferred. Forexample, when the compound has acid functionality, inorganic salts suchas alkali metal salts (for example, sodium salt, potassium salt, etc.),alkaline earth metal salts (for example, calcium salt, magnesium salt,etc.), etc. and ammonium salts may be proposed; and when the compoundhas basic functionality, salts with inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,etc., and salts with organic acids such as acetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc. may be proposed.

Processes for Production

Processes for the production of the compounds of the present inventionwill now be described.

Starting materials and reagents used in any of the steps in thefollowing processes for production and the obtained compounds may be inthe form of a respective salt. As examples of such salts, the same kindsof salts as the said salts of the compounds of the present invention maybe proposed.

When the compound obtained in any of the steps is the free compound,said free compound can be converted to a target salt using by itself awell-known process. Conversely, when the compound obtained in any of thesteps is a salt, said salt can be converted to the free body or anothertype of intended salt by itself well-known process.

The compound obtained in any of the steps may be used in the followingreaction either still in the form of the reaction liquid, or afterobtaining the crude product. Alternatively, the compound obtained ineach of the steps can be isolated and/or purified from the reactionmixture by a separation means such as concentration, crystallization,recrystallization, distillation, solvent extraction, fractionating,chromatography, etc. in accordance with conventional procedures.

If a raw material or reagent in any of the steps is a marketed,commercial product, then such a product can be used.

In the reactions in any of the steps, the reaction time can differdepending on the reagent and solvent used, but unless otherwisespecifically stated, said reaction time is usually 1 min to 48 hours,preferably 10 mins to 8 hours.

In the reactions in any of the steps, the reaction temperature candiffer depending on the reagent and solvent used, but unless otherwisespecifically stated, said reaction temperature is usually −78° C. to300° C., preferably −78° to 150° C.

In the reactions in any of the steps, the pressure can differ dependingon the reagent and solvent used, but unless otherwise specificallystated, said pressure is usually 1 atmosphere to 20 atmospheres,preferably 1 atmosphere to 3 atmospheres.

In the reactions in any of the steps, for example, a microwavesynthesizing apparatus such as an Initiator made by the BiotageCorporation may be used. The reaction temperature can differ dependingon the reagents and solvent used, but unless otherwise specificallystated, the reaction temperature is usually room temperature to 300° C.,preferably 50° to 250° C. The reaction time can differ depending on thereagents and solvent used, but unless otherwise specifically stated, thereaction time is usually 1 min to 48 hours, preferably 1 min to 8 hours.

In the reactions in any of the steps, unless otherwise specificallystated to the contrary, 0.5 equivalents to 20 equivalents, morepreferably 0.8 equivalents to 5 equivalents reagent are used withrespect to the substrate. When the reagent is used as a catalyst, 0.001equivalents to 1 equivalent, more preferably 0.01 equivalents to 0.2equivalents reagent is used with respect to the substrate. When thereagent serves as the reaction solvent, the reagent is used in theamount of solvent.

In the reactions in any of the steps, unless otherwise specificallystated to the contrary, such reactions may be performed in the absenceof solvent or with dissolution or suspension in a suitable solvent. Asspecific examples, those solvents described later in the Examples, orthose given below may be proposed:

Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.,

Ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane, etc.,

Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.,

Saturated hydrocarbons: cyclohexane, hexane, etc.,

Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.,

Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.,

Nitriles: acetonitrile, etc.,

Sulfoxides: dimethyl sulfoxide, etc.,

Aromatic organic bases types: pyridine, etc.,

Acid anhydrides: acetic anhydride, etc.,

Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.,

Inorganic acids: hydrochloric acid, sulfuric acid, etc.,

Esters: ethyl acetate, etc.,

Ketones: acetone, methyl ethyl ketone, etc.,

Water.

Said solvents may be used in a combination of two or more thereof insuitable proportions.

When base is used in the reactions in any of the steps, for example, abase shown below or a base described in the Examples may be used.

Inorganic bases: sodium hydroxide, magnesium hydroxide, sodiumcarbonate, calcium carbonate, sodium bicarbonate, etc.,

Organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine,

N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.,

Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.,

Alkali metal hydrides: sodium hydride, etc.,

Metallic amides: sodium amide, lithium diisopropylamide, lithiumhexamethyl disilazide, etc.,

Organolithiums: n-butyllithium, etc.

When acid or acid catalyst is used in the reactions in any of the steps,for example, an acid or acidic catalyst shown below, or an acid oracidic catalyst described in the Examples, may be used.

Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid, etc.,

Organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphor sulfonic acid, etc.,

Lewis acids: Boron trifluoride diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride lead, anhydrousiron chloride, etc.

The reactions in any of the steps are not restricted unless otherwisespecifically stated, and can be performed in accordance with processesthat are in themselves well-known, for example, processes as describedin the Fifth Series of Experimental Chemistry, Vol. 13 to 19, (TheChemical Society of Japan); New Experimental Chemistry Course, Vol. 14to 15 (The Chemical Society of Japan); Fine Organic Chemistry, RevisedSecond Edition (L. F. Tietze, Th. Eicher, Nankodo); Revised Organic NameReactions, their mechanism and essence (Hideo Togo, Kodansha); ORGANICSYNTHESES Collective Volume I to VII (John Wiley & Sons Inc); ModernOrganic Synthesis in the Laboratory A Collection of StandardExperimental Procedures (Jie Jack Li, OXFORD UNIVERSITY Publication);Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (ElsevierJapan Co. Ltd.); Strategic Applications of Named Reactions in OrganicSynthesis (Translation Supervised by Tomioka Kiyoshi, Kagaku DojinPublication), Comprehensive Organic Transformations (VCH Publishers Inc)1989, etc., or in accordance with processes as described in theExamples.

In each step, protecting or deprotecting reactions for the functionalgroups are performed in accordance with processes which are inthemselves well-known, for examples, processes described in “ProtectiveGroups in Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene,Peter G. M. Wuts) published by Wiley-Interscience in 2007; or“Protecting Groups 3rd Ed.” (P. J. Kocienski) published by Thieme in2004; or in accordance with processes described in the Examples. In thecase of hydroxy groups of protected alcohols and phenolic hydroxygroups, for example, ether groups such as methoxymethyl ether, benzylether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether, etc.;carboxylate ester groups such as acetic acid ester, etc.; sulfonic acidester groups such as methanesulfonic ester, etc.; carbonic acid estergroups such as tert-butyl carbonate, etc., and the like, may beproposed.

In the case of carbonyl groups of protected aldehydes, for example,acetal groups such as dimethyl acetal, etc.; cyclic acetal groups suchas 1,3-dioxane, etc., and the like may be proposed.

In the case of carbonyl groups of protected ketones, for example, ketalgroups such as dimethyl ketal, etc., cyclic ketal groups such as1,3,-dioxane, etc., oxime group such as O-methyloxime, etc., hydrazonegroups such as N,N-dimethylhydrazone, etc., and the like, may beproposed.

In the case of protected carboxyl groups, for example, ester groups suchas methyl ester, etc., amide groups, etc. such as N,N-dimethyl amide,etc., and the like, may be proposed.

In the case of protected thiols, for example, ether groups such asbenzylthio ether, etc., ester groups such as thioacetic acid ester,thiocarbonate, thiocarbamate, etc., and the like may be proposed.

In the case of protected amino groups and aromatic heterocycles such asimidazole, pyrrole, indole, etc., carbamate groups such as benzylcarbamate, etc., amide groups such as acetamide, etc., alkylamine groupssuch as N-triphenylmethylamine, etc., sulfonamide groups such as methanesulfonamide, etc., and the like, may be proposed.

The elimination of the protecting groups can be carried out using itselfwell-known process, for example a process using acid, base, UV light,hydrazine, phenylhydrazine, sodium N-methyl dithiocarbamate,tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide(for example, trimethylsilyl iodide, trimethylsilyl bromide), orreducing method or the like.

When a reducing reaction is performed in any of the steps, the reducingagent used may comprise, for example, a metal hydride such as lithiumaluminum hydride, sodium acetoxy borohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride, acetoxyborohydride tetramethylammonium, etc., a borane such as boranetetrahydrofuran complex, etc., Raney nickel, Raney cobalt, hydrogen,formic acid, etc. When a carbon-carbon double bond or triple bond isbeing reduced, a process using a catalyst such as a palladium-carboncatalyst, Lindlar catalyst, etc. may be applied.

When an oxidation reaction is performed in any of the steps, theoxidizing agent used may comprise a peroxy acid such asm-chloroperbenzoic acid (MCPBA), hydrogen peroxide,tert-butylhydroperoxide, etc., a perchlorate salt such astetrabutylammonium perchlorate, etc., a chlorate salt such as sodiumchlorate, etc., a chlorite such as sodium chlorite, etc., a periodatesuch as sodium periodate, etc., a high atomic valency iodine reagentsuch as iodosobenzene, etc., a reagent containing manganese such asmanganese dioxide, potassium permanganate, etc., a lead compound such aslead tetraacetate, etc., a reagent containing chromium such aspyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jonesreagent, etc., a halogen compound such as N-bromo succinimide (NBS),etc., oxygen, ozone, sulfur trioxide/pyridine complex, osmium tetroxide,selenium dioxide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc.

When a radical cyclization reaction is performed in any of the steps,the radical initiator which is used may comprise an azo compound such asazobisisobutyronitrile (AIBN), etc.; a water-soluble radical initiatorsuch as 4-4′-azobis-4-cyanopentanoic acid (ACPA), etc.; triethyl boronin the presence of air or of oxygen; benzoyl peroxide, etc. Moreover, asfar as the radical reaction reagent used is concerned, tributylstannane,tris trimethylsilyl silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane,samarium iodide, etc. may be proposed.

When a Wittig reaction is performed in any of the steps, an alkylidenephosphorane, etc. may be proposed as the Wittig reagent used. Analkylidene phosphorane can be prepared by itself a well-known process,such as, for example, the reaction of a phosphonium salt with strongbase.

In any of the steps, when a Horner-Emmons reaction is performed, thereagent used may comprise a phosphonoacetic acid ester such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate, etc., a basesuch as an alkali metal hydride, an organolithium, etc.

When a Friedel-Crafts reaction is performed in any of the steps, thereagent used may comprise a combination of Lewis acid and acid chlorideor a combination of Lewis acid and alkylating agent (for example alkylhalide, alcohol, olefin, etc.) may be proposed. Alternatively, anorganic acid and/or inorganic acid can be used instead of the Lewisacid, and an acid anhydride such as acetic anhydride, etc. can be usedinstead of the acid chloride.

When an aromatic nucleophilic substitution reaction is performed in anyof the steps, as the reagent used a nucleophilic reagent (for example,amine, imidazole, etc.) and base (for example, organic base, etc.) maybe used.

In any of the steps, when a nucleophilic addition reaction using acarbanion, a nucleophilic 1,4-addition reaction using a carbanion(Michael addition reaction) or a nucleophilic substitution reactionusing a carbanion, is performed, as the base used to generate thecarbanion, an organolithium, metal alkoxide, inorganic base, organicbase, etc. may be proposed.

When a Grignard reaction is performed in any of the steps, the Grignardreagent may comprise an aryl magnesium halide such as phenylmagnesiumbromide, etc., an alkylmagnesium halide such as methyl magnesiumbromide, etc. The Grignard reagent can be prepared by itself well-knownprocess, for example, by reacting metal magnesium with alkyl halide oraryl halide in tetrahydrofuran or ether as solvent.

In any of the steps, when a Knoevenagel condensation reaction isperformed, the reagents used may comprise an active methylene compoundwith two electrophilic groups (for example, malonic acid, diethylmalonate, malonitrile, etc.) and base (for example organic base, metalalkoxide, inorganic base).

When a Vilsmeier-Haack reaction is performed in any of the steps, thereagent used may comprise a phosphorus oxychloride and an amidederivative (for example N,N-dimethylformamide, etc.).

In any of the steps, when an azide forming reaction is performed with analcohol, alkyl halide or sulfonate, as the azide forming agent which isused, diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodiumazide, etc. may be proposed. For example, when an alcohol is subjectedto azide formation, for example, a process using diphenylphosphorylazide and 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a process usingtrimethylsilyl azide and Lewis acid, may be applied.

When a reductive amination reaction is performed in any of the steps,the reducing agent used may comprise sodium acetoxyborohydride, sodiumcyanoborohydride, hydrogen, formic acid, etc. When the substrate is asamine compound, as the carbonyl compound used, in addition toparaformaldehyde, an aldehyde such as acetaldehyde, etc., a ketone suchas cyclohexanone, etc. may be proposed. When the substrate is a carbonylcompound, as the amine used, ammonia, a primary amine such asmethylamine, etc., or a secondary amine such as dimethylamine, etc., orthe like may be proposed.

When a Mitsunobu reaction is performed in any of the steps, as thereagent used, azodicarboxylic acid ester (for example, diethylazodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) andtriphenylphosphine may be used.

In any of the steps, when an esterification reaction, amidation reactionor urea-forming reaction is performed, as the reagent which is used, ahalogenated acyl compound such as acid chloride, acid bromide, etc., anactivated carboxylic acid compound such as acid anhydride, active ester,sulfate ester, etc. may be proposed. As carboxylic acid activatingagent, a carbodiimide-based condensing agent such as1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD),etc.; a triazine-based condensing agent such as4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl morpholiniumchloride-n-hydrate (DMT-MM); a carbonate ester-based condensing agentsuch as 1,1-carbonyldiimidazole (CDI), etc.; diphenylphosphorazidate(DPPA); benzotriazol-1-yloxy-tris dimethylamino phosphonium salt (BOPreagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);thionyl chloride, a halo formic acid lower alkyl ester such as ethylchloroformate, etc.; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or combinations ofthese, etc. may be proposed. When a carbodiimide-based condensing agentis used, an additive such as 1-hydroxy benzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), etc. may also be addedto the reaction.

When a coupling the reaction is performed in any of the steps, as themetal catalyst used, a palladium compound such as palladium (II)acetate, tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenylphosphine)palladium (II),dichlorobis(triethylphosphine)palladium (II),tris(dibenzylideneacetone)dipalladium (0),1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, palladium(II) acetate, etc.; a nickel compound such astetrakis(triphenylphosphine)nickel (0), etc.; a rhodium compound such astris(triphenylphosphine)rhodium (III) chloride, etc.; a cobalt compound;a copper compound such as copper oxide, copper (I) iodide, etc.; aplatinum compound, etc. may be proposed. Moreover, base may be added tothe reaction, and as such base, inorganic bases, etc. may be proposed.

When a thiocarbonylation reaction is performed in any of the steps, asthiocarbonylation agent, typically phosphorous pentasulfide is used, butother than phosphorous pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as 2,4-bis(4-methoxyphenyl-1, 3, 2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) may be used.

When a Wohl-Ziegler reaction is performed in any of the steps, thehalogenating agent, may comprise N-iodosuccinimide, N-bromosuccinimide(NBS), N-chlorosuccinimide (NCS), bromine, chlorosulfuric acid, etc.Moreover, the reaction can be accelerated by applying heat, light,radical initiator such as benzoyl peroxide, azobisisobutyronitrile, etc.to the reaction.

When a hydroxy group halogenation is performed in any of the steps, thehalogenating agent used comprises an acid halide compound of aninorganic acid with hydrohalic acid; specific examples include in thecase of chlorination, hydrochloric acid, thionyl chloride, phosphorusoxychloride, etc.; and in the case of bromination, 48% hydrobromic acid,etc. Moreover, a process to obtain alkyl halide from alcohol based onthe action of triphenylphosphine and carbon tetrachloride or carbontetrabromide, etc. may be used. Alternatively, a method via a two stagereaction may be applied, wherein an alcohol is first converted tosulfonic acid ester, and then the alkyl halide synthesized by reactionwith lithium bromide, lithium chloride or sodium iodide.

When an Arbuzov reaction is performed in any of the steps, the reagentused may comprise an alkyl halide such as ethyl bromoacetate, etc., aphosphite such as triethyl phosphite or tri(isopropyl) phosphite, etc.

When a sulfonic acid ester forming reaction is performed in any of thesteps, examples of sulfonylating agent used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride,p-toluenesulfonic acid anhydride and the like.

When a hydrolysis reaction is performed in any of the steps, an acid orbase is used as the reagent. Moreover, when acid hydrolysis oftert-butyl ester is performed, formic acid and/or triethylsilane, etc.can be added in order to trap by-produced tert-butyl cations usingreduction.

When a dehydration reaction is performed in any of the steps, as thedehydrating agent used, sulfuric acid, diphosphorus pentoxide,phosphorus oxychloride, N,N-dicyclohexylcarbodiimide, alumina,polyphosphoric acid, etc. may be proposed.

Compound (I) can be produced by the following process from Compound (2).

(wherein, LG is a leaving group, and the other symbols have the samesaid meanings)

As leaving group represented by LG, for example, a halogen atom(chlorine atom, bromine atom, iodine atom, etc.), substitutedsulfonyloxy group (C₁₋₆ alkylsulfonyloxy group such as methanesulfonyloxy, ethane sulfonyloxy, etc.; C₆₋₁₄ aryl sulfonyloxy group suchas benzene sulfonyloxy, p-toluene sulfonyloxy, etc.; C₇₋₁₆ aralkylsulfonyloxy group, etc. such as benzyl sulfonyloxy group, etc.), acyloxygroup (acetoxy, benzoyloxy, etc.) and the like may be proposed.

Compound (4) can be produced from Compound (2) by performing asubstitution reaction using Compound (3) in the presence of base.

Compound (3) can be synthesized by the following process from Compound(5).

(wherein, LG has the same said meaning)

Compound (5) may be a commercial product, or can be produced by awell-known process or a process based on such a process.

Compound (2) can be synthesized in accordance with itself well-knownmethod; and for example, Compound (2a) can be produced by the followingprocess from Compound (7).

(wherein, each symbol has the same said meaning)

Compound (9) can be produced from Compound (8) by a substitutionreaction using thioacetic acid or a thioacetate salt, in the presence ofbase. As the salt of thioacetic acid, the potassium salt, sodium salt,etc. may be proposed.

Compound (7) can be synthesized in accordance with itself well-knownmethod; and for example, Compound (7a) can be synthesized in accordancewith a process which is well-known in the literature (SyntheticCommunications, 16(2), 149-156 (1986)).

Moreover, Compound (7), when Compound (7b), can be synthesized inaccordance with a process well-known in the literature(WO2011/093512A1).

Compound (2), when Compound (2b), can be produced by the followingprocess from Compound (12).

(wherein, PG is a protecting group, and the other symbols have the samesaid meanings)

Compound (13) can be produced from Compound (12) by carbonylation usinga carbonylation reagent in the presence of base. As carbonylationreagent, diethyl carbonate, ethyl chloroformate, acetyl chloride, aceticanhydride, N,N-dimethylformamide may be proposed.

Compound (15) can be produced by a substitution reaction of Compound(14) using thioacetic acid or a thioacetate salt, in the presence ofbase. As the salt of thioacetic acid, the potassium salt, sodium salt,etc. may be proposed.

Compound (19) can be produced from Compound (18) using anacetal-exchange reaction in the presence of acid.

Compound (18) can be synthesized by the following process from Compound(20).

(wherein, each symbol has the same said meaning)

Compound (12) and Compound (20) may be commercial products, or can beproduced by well-known processes or processes based on such processes.

Compound (2), when Compound (2c), can be produced by the followingprocess from Compound (16).

(wherein, each symbol has the same said meaning).

Compound (4), when Compound (4b), can be produced by the followingprocess from Compound (2b).

(wherein, R⁴ is an optionally substituted alkyl group, and the othersymbols have the same said meanings)

Compound (4a) can be produced from Compound (2b) by a substitutionreaction using Compound (3) in the presence of base.

Compound (4b) can be produced from Compound (4a) by alkylation usingCompound (22) in the presence of base.

A marketed product may be used as Compound (22) or it can be prepared bya well-known process or a process based on such a process.

When Compound (I) includes optical isomers, stereoisomers, positionalisomers or rotational isomers, these are also included within Compound(I), and also, these can be obtained as respectively isolated productsby in themselves well-known synthesis techniques and separationaltechniques (for example, concentration, solvent extraction, columnchromatography, recrystallization, etc.). For example, when opticalisomers are present in Compound (I), the optical isomers resolved fromsaid compound are also included within Compound (I).

Optical isomers can be produced using in themselves well-knownprocesses. More specifically, optical isomers may be obtained by usingan optically active intermediate or by resolving the final racemateproduct in accordance with conventional procedures.

As optical resolution method, itself well-known process, for example afractional crystallization method, chiral column method, diastereomermethod, etc. is used.

1) Fractional Crystallization Method

A method wherein a salt is formed between the racemate and an opticallyactive compound (for example, (+)-mandelic acid, (−)-mandelic acid,(+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethyl amine,(−)-1-phenethyl amine, cinchonine, (−)-cinchonidine, brucine, etc.), andthis then separated by a fractional crystallization method, and then inaccordance with requirements, the free optical isomer is obtained via aneutralization step.

2) Chiral Column Method

A method wherein the racemate or a salt thereof is separated using acolumn for optical isomer separation (a chiral column) For example, inthe case of liquid chromatography, the mixture of optical isomers isadded to ENANTIO-OVM (made by Tosoh Corp.) or one of the CHIRAL series(made by Daicel Chemical Industries Ltd.), and development performedwith a solution comprising one of, or a mixture of, water, variousbuffers (for example phosphate-buffer solution, etc.) and organicsolvent (for example, ethanol, methanol, 2-propanol, acetonitrile,trifluoroacetic acid, diethylamine, etc.), and the optical isomersthereby separated. Moreover, for example, in the case of gaschromatography, a chiral column such as CP-Chirasil-DeX CB (made by GLSciences Inc.), etc. may be used to cause separation.

3) Diastereomer Method

A method wherein the racemic mixture is formed into a mixture ofdiastereomers by a chemical reaction with an optically active reagent,and then this mixture formed into the single substances via conventionalseparational means (for example, fractional crystallization,chromatography method, etc.), etc., and then the optical isomersobtained by cleaving the optically active reagent position by a chemicaltreatment such as hydrolysis reaction, etc. For example, when compound(I) contains an hydroxy or a primary or secondary amino within themolecule, the diastereomer of the ester or amide compound isrespectively obtained by subjection of said compound to a condensationreaction with an optically active organic acid (for example, MTPA[α-methoxy-α-(trifluoromethyl)phenyl acetic acid], (−)-methoxy aceticacid, etc.). On the other hand, when compound (I) contains a carboxygroup, the diastereomer of the ester or amide is respectively obtainedby subjection of said compound to a condensation reaction with anoptically active amine or alcohol reagent. The separated diastereomermay then be converted into the optical isomer of original compound bysubjection to hydrolysis with acid or hydrolysis with hydrolysis.

Compound (I) may be crystalline.

Crystals of compound (I) can be produced by causing crystallization bysubjecting compound (I) to itself well-known crystallization process.

Wherein as crystallization method, for example a method ofcrystallization from solution, a method of crystallization from vapor, amethod of crystallization method from a melt, etc., may be proposed.

As said “method of crystallization from solution”, a method is generallyapplied wherein using a factor relating to the solubility of thecompound (solvent composition, pH, temperature, ionic strength, redoxstate, etc.) or the quantity of solvent, a transition from anunsaturated state to a super-saturated state is achieved; specificexamples include, for example, a concentration method, slow-coolingmethod, reaction method (diffusion method, electrolysis method),hydrothermal cultivation method, fusing method, etc. As the solventwhich is used, for example, an aromatic hydrocarbon (for example,benzene, toluene, xylene, etc.), halogenated hydrocarbon (for example,dichloromethane, chloroform, etc.), saturated hydrocarbon (for example,hexane, heptane, cyclohexane, etc.), ether (for example, diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrile (forexample, acetonitrile, etc.), ketone (for example, acetone, etc.),sulfoxide (for example, dimethyl sulfoxide, etc.), acid amide (forexample N,N-dimethylformamide, etc.), ester (for example ethyl acetate,etc.), alcohol (for example methanol, ethanol, 2-propanol, etc.), water,etc. may be proposed. These solvents may be used singly or a mixture oftwo or more thereof in a suitable proportion (for example 1:1 to 1:100(volume ratio)) may be used. Seed crystals can be used in accordancewith requirements.

As said “method of crystallization from vapor”, for example, avaporization method (sealed tube method, gas flow method), gas phasereaction method, chemical transport method and the like methods may beproposed.

As said “method of crystallization from melt”, for example, a normalfreezing method (pull-up method, temperature gradient method, Bridgmanmethod), zone melting method (zone leveling method, float zone method),special growth method (VLS method, liquid phase epitaxy method), etc.may be proposed.

As ideal example of crystallization method, a method wherein compound(I) is dissolved in a suitable solvent (alcohol, etc., such as methanol,ethanol, etc.) at a temperature of 20 to 120° C., and then the obtainedsolution is cooled to a temperature below the temperature when itdissolved (for example 0 to 50° C., preferably 0 to 20° C.), etc., maybe proposed.

The crystals of the present invention obtained in this way can, forexample, be isolated by filtration, etc.

A crystallographic analysis method based on powder X-ray diffraction isgenerally used as a method of analyzing the obtained crystals. Moreover,as a method of determining the crystal orientation, a mechanical methodor optical method or the like may be proposed.

The crystals of compound (I) obtained by said methods of production havehigh purity and high quality, have low hygroscopicity, and, theirquality does not deteriorate even if stored for a long time underambient conditions, and they have extremely excellent safety. Moreover,the biological properties (for example pharmacokinetics (absorptivity,distribution, metabolism, excretion), drug efficacy expression, etc.)are excellent; properties which are extremely useful in a drug.

Prodrugs of compound (I) are compounds which are converted to compound(I) by reactions due to gastric acid or enzymes or the like underphysiological conditions; namely compounds transformed into compound (I)due to enzymatic oxidation, reduction, hydrolysis, etc., occurring, andcompounds transformed into compound (I) due to hydrolysis caused bygastric acid, etc., occurring. Examples of prodrugs of compound (I)include compounds wherein an amino group of compound (I) has beenacylated, alkylated or phosphorylated [for example, compounds wherein anamino group of compound (I) has been eicosanoylated, alanylated,pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidyl methylated,pivaloyloxymethylated or tert-butylated]; compounds wherein a hydroxygroup of compound (I) has been acylated, alkylated, phosphorylated orborylated [for example, compounds wherein a hydroxy group has beenacetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.]; andcompounds wherein a carboxyl group of compound (I) has been formed intoan ester or amide [for example, compounds wherein a carboxyl group ofcompound (I) has been formed into an ethyl ester group, phenyl estergroup, carboxymethyl ester group, dimethylaminomethyl ester group,pivaloyloxymethyl ester group, ethoxycarbonyloxyethyl ester group,phthalidyl ester group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl estergroup, cyclohexyloxycarbonylethyl ester group, or methylamide group],and the like. These compounds can be produced from compound (I) bywell-known processes.

Moreover, the prodrugs of compound (I) may be those that transform intocompound (I) under physiological conditions in the same way as describedin “Development of Pharmaceuticals” (Hirokawa Publishing, 1990) vol. 7,Molecular Design 163-198

In this specification, the compounds (I) and the prodrugs of compounds(I) may be collectively termed “the compounds of the present invention”.

Compound (I) may be any of hydrate, non-hydrate, solvate andnon-solvate.

Compounds which are isotopically labeled (for example, with ³H, ¹⁴C,³⁵S, ¹²⁵I, etc.) are also included in compound (I).

Moreover, compounds substituted with heavy hydrogen in which ¹H has beenreplaced by ²H (D) are also included within compound (I).

Tautomers are also included within compound (I).

Compound (I) may be present as a pharmacologically acceptable co-crystalor co-crystalline salt. Wherein, co-crystal and co-crystalline saltdenotes a crystalline substance constructed from at least two uniquesolids at room temperature having various different physicalcharacteristics (for example, structure, melting point, heat of fusion,hygroscopicity, solubility and stability, etc.). Co-crystals andco-crystalline salts can be produced in accordance with well-knowncrystallization methods. Compound (I) may be used as PET tracer.

The compounds of the present invention have excellent TLR4 signalinginhibitory action, and so said compounds are useful as safe drugs basedon the said action.

Accordingly, the TLR4 signaling inhibiting substances in the presentinvention can be used with respect to mammalian organisms (for example,mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, or thelike) as preventive and/or therapeutic agents of, for example,autoimmune disease and/or inflammatory disease, and diseases such asinfectious disease, cardiac disease, central nervous system disease,hypoimmunity and the like; for example, sepsis including serious sepsis,septic shock, septicemia, endotoxic shock, exotoxic shock, systemicinflammatory response syndrome (SIRS), compensatory antiinflammatoryreaction syndrome (CARS), burn injury, trauma, postoperativecomplication, cardiac failure, shock, hypotension, rheumatoid arthritis,osteoarthritis, gastritis, ulcerative colitis, peptic ulcer,stress-induced peptic ulcer, Crohn's disease, autoimmune disease, graftrejection after organ transplantation, ischemia-reperfusion injury(IRI), liver injury (acute liver injury (ALI), ACLF), acute coronarymicrovascular embolism, shock-induced vascular embolism (disseminatedintravascular coagulation (DIC) or the like), ischemic encephalopathy,arteriosclerosis, pernicious anemia, Fanconi anemia, sickle cell anemia,pancreatitis, nephrotic syndrome, acute and chronic nephropathy,nephritis, renal failure, insulin dependent diabetes mellitus,non-insulin dependent diabetes mellitus, hepatic porphyria, alcoholpoisoning, Parkinson's disease, chronic leukemia, acute leukemia, tumor,myeloma, infant and adult respiratory distress syndrome, chronicobstructive pulmonary disease, dementia, Alzheimer's disease, multiplesclerosis, optic nerve myelitis, Vitamin E deficiency, ageing, sunburn,muscular dystrophy, myocarditis, cardiomyopathy, myocardial infarction,myocardial infarction sequellae, osteoporosis, pneumonia, hepatitis,psoriasis, pain, cataract, influenza infection, malaria, humanimmunodeficiency virus (HIV) infection, radiation damage, burn,hypercalcemia, ankylosing spondylitis, osteopenia, Paget's disease,osteomalacia, bone fracture, acute bacterial meningitis, Helicobacterpylori infection, invasive Staphylococcus infection, tuberculosis,systemic fungal infection, herpes simplex viral infection,varicella-zoster viral infection, human papilloma virus infection, acuteviral encephalitis, encephalitis, meningitis, hypoimmunity accompanyinginfection, bronchial asthma, atopic dermatitis, allergic rhinitis,reflux esophagitis, fever, hypercholesterolemia, hyperglyceridemia,hyperlipidemia, diabetic complications, diabetic nephropathy, diabeticneuropathy, diabetic retinopathy, gout, gastric atony, hemorrhoids,systemic lupus erythematosus, spinal cord injury, insomnia,schizophrenia, epilepsy, cirrhosis, hepatic insufficiency, unstableangina, cardiac valvular disease, thrombocytopenia or hypotension due todialysis, acute ischemic cerebral apoplexy, acute cerebral thrombosis,cancer metastasis, urinary bladder cancer, breast cancer, uterinecervical cancer, colorectal cancer, gastric cancer, ovarian cancer,prostate cancer, small cell lung cancer, non-small cell lung cancer,malignant melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, sideeffects due to anticancer agent and immunosuppressant drugadministration, chronic obstructive pulmonary disease, cystic fibrosis,pulmonary fibrosis, autoimmune hemolytic anemia, meningitis,inflammatory pulmonary disease (for example, silicosis, pulmonarysarcoidosis, tuberculosis), endometriosis, cachexia (for example,cachexia due to infection, cancerous cachexia, cachexia due to acquiredimmunodeficiency syndrome), cancer pain, Addison's disease, acute paindue to inflammation, pain due to chronic inflammation, post-operativepain (incision wound pain, deep pain, visceral pain, chronicpost-operative pain, or the like), myalgia (myalgia accompanying chronicpain, stiff neck, or the like), arthralgia, toothache, temporomandibulararthralgia, headache (migraine headache, tension headache, headacheaccompanying pyrexia, headache accompanying hypertension), visceral pain(cardialgia, anginal pain, abdominal pain, kidney pain, urinary tractpain, bladder pain), pain of the obstetric and gynecological area(intermenstrual pain, dysmenorrheal and labour pain), neurogenic pain(spinal disc herniation, nerve root pain, post-herpes zoster neuralgia,trigeminal neuralgia, lumbago, or the like), chemotherapys ((taxaneanticancer drugs (for example, paclitaxel (taxol), docetaxel), vincaalkaloid anticancer drugs (for example, vincristine, vinblastine),platinum preparations (for example, cisplatin, carboplatin,oxaliplatin), molecular target drug (for example, bortezomib) or thelike))-induced peripheral neuropathy (CIPN) and associated neurologicalsymptoms (chemotherapy-induced neuropathic pain (CINP) (dysesthesia suchas numbness and/or pain (for example, muscle pain, nerve pain))), reflexsympathetic atrophy, complex local pain syndrome, pituitary glandabscess, thyroiditis, peritonitis, erythema nodosum), allergicconjunctivitis, pollinosis, metal allergy, exudative otitis media,Meniere's disease, contact dermatitis, anaphylaxis, urticaria,myasthenia gravis, Sjogren's syndrome, Basedow's disease, leukocyteabnormality, renal tubulointerstitial disorder (including fibrillarypathology), acute coronary artery syndrome, atherosclerotic aorticaneurysm, cardiac anaphylaxis, deep vein thrombosis, ophthalmologicdiseases (for example, pterygium, spring catarrh, dry eye, or the like),food allergy, NUD (Non Ulcer Dyspepsia), gastric MALT lymphoma, ulcerdue to non-steroid anti-inflammatory drug, gastric hyperacidity, gastrichyperacidity and ulcer due to postoperative stress, obesity, edema,granuloma, atopic myelitis, neurofibroma, nasal mucosalhypersensitivity, osteoarthritis, scleroderma, or the like. Moreover,the TLR4 signaling inhibiting substance of the present invention canalso be used for increasing efficiency of in vitro fertilization.

Wherein, the “prevention” of said disease means, for example, theadministration of a drug containing the compound of the presentinvention to a patient who has not yet developed the said disease but isthought to be of high risk of onset due to some factor related to thesaid disease, or to a patient who has developed the disease but withoutsubjective symptoms, or the administration of a drug containing thecompound of the present invention to a patient who, following treatmentof the said disease, is concerned about recurrence of said disease.

A drug containing the compound of the present invention can be used as acompound of the present invention alone or as pharmaceutical compositionof a mixture of a compound of the present invention andpharmacologically acceptable carrier, in accordance with well-knownprocesses for the production of drug preparations (for examples,processes in accordance with Pharmacopeia of Japan). Pharmaceuticalcompositions containing the compound of the present invention can besafely administered orally or parenterally (example, intravenously,intramuscularly, subcutaneously, by intraorgan administration,intranasally, intracutaneously, by eye drops, intracerebrally,endorectally, intravaginally, intraperitoneally, by intratumoradministration, by tumor proximal administration, by administration atthe focus of the disease, or the like); for example as a tablet(including sugar coated tablet, film coated tablet, sublingual tablet,oral cavity disintegration tablet, buccal tablet), pill, powder,granules, encapsulated formulation (including soft capsule agent andmicrocapsule agent), troche agent, syrup, liquid agent (including organpreservation solution and organ perfusion solution), emulsion,suspending agent, controlled release preparation (for example, rapidrelease preparation, slow release preparation, controlled-releasemicrocapsule agent), aerosol, film agent (for example, oral cavitydisintegration film, oral mucosal patch), injectable (for example,subcutaneous injection agent, intravenous injection agent, intramuscularinjection agent, intraperitoneal injection agent), drip infusion agent,percutaneous absorption preparation, cream agent, ointment, lotion,patch, suppository (for example, anal suppository, vaginal suppository),pellet, transnasal agent, transpulmonary agent (inhalant), instillation,or the like.

The content of the compound of the present invention in the drug of thepresent invention is about 0.01 wt. % to about 100 wt. % of the totaldrug. Said dose differs depending on the administration subject,administration route, disease, or the like, however, for example, withrespect to a patient with chemotherapy-induced peripheral neuropathy(CIPN), chemotherapy-induced neuropathic pain (CINP), liver injuryand/or ischemia-reperfusion injury (IRI) (about 60 kg in weight), asorally administered agent, about 0.01 mg/kg body weight to about 500mg/kg body weight, preferably about 0.1 mg/kg body weight to about 50mg/kg body weight, more preferably about 1 mg/kg body weight to about 30mg/kg body weight as effective ingredient (compound (I)) per day, may beadministered once a day or divided into several times.

As the pharmacologically acceptable carrier which may be used in theproduction of the drug of the present invention, various conventionallyused organic or inorganic carrier substances may be proposed, and forexample, excipients, lubricants, binding agents and disintegratingagents in solid preparations; and, solvents, solubilizers, suspendingagents, isotonizing agents, buffer agents and analgesics and the like inliquid preparations may be proposed. Furthermore, additives such asconventional preservatives, anti-oxidant, colorant, sweetener,adsorbent, wetting agent, or the like can be suitably used in a suitablequantity in accordance with requirements.

The dose when the pharmaceutical composition of the present invention isa slow release preparation varies in various ways depending on the kindand content of compound (I), agent form, duration of drug release,administration subject animal (mammalian organism such as mouse, rat,hamster, guinea pig, rabbit, cat, dog, cow, horse, pig, sheep, monkey,human or the like) and object of administration, however, for example,when applied by a parenteral administration route, the administrationpreparation may be designed so that about 0.1 to about 100 mg ofcompound (I) is released in a week.

Examples of excipient include lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid, etc.

Examples of lubricant include magnesium stearate, calcium stearate,talc, colloidal silica, etc.

Examples of binding agent include crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium, etc.

Examples of disintegrating agent include starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethyl starch sodium,L-hydroxypropylcellulose, etc.

Examples of solvent include water used for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil, etc.

Examples of solubilizer include polyethyleneglycol, propylene glycol,D-mannitol, benzyl benzoate, ethanol, tris aminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate, etc.

Examples of suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylamino propionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate, etc., hydrophilic macromolecules such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropylcellulose, etc., and the like.

Examples of isotonizing agent include glucose, D-sorbitol, sodiumchloride, glycerol, D-mannitol, etc.

Examples of buffer agent include buffers such as phosphates, acetates,carbonates, citrates, etc.

Examples of analgesic include benzyl alcohol, etc.

Examples of preservative include parahydroxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid, etc.

Examples of anti-oxidant include sulfite, ascorbic acid, α-tocopherol,etc.

During the prevention and/or treatment of various diseases, thecompounds of the present invention can be used together with otheragents. Hereinafter, drugs which are used when the compounds of thepresent invention are used concomitantly with other drugs will bereferred to as “combined used agents of the present invention”.

The TLR4 signaling inhibiting substance can be co-used concomitantlywith other drugs. Examples of such co-used drugs include antibacterialagents, antifungal agents, nonsteroidal antiinflammatory drugs, steroiddrugs, anticoagulants, antiplatelet drugs, thrombolytic drugs,immunomodulators, antiprotozoal drugs, antitussive-expectorant drugs,sedatives, anesthetic drugs, narcotic antagonists, antiulcer drugs,drugs for treating hyperlipidemia, drugs for treating arteriosclerosis,HDL elevating drugs, unstable plaque stabilization drugs, myocardialprotective agents, drugs for treating hypothyroidism, drugs for treatingnephrotic syndrome, drugs for treating chronic renal failure, diuretics,antihypertensive drugs, drugs for treating cardiac failure, musclerelaxants, antiepileptic drugs, cardiotonics, vasodilators,vasoconstrictors, drugs for treating arrhythmia, drugs for treatingdiabetic mellitus, vasopressor, tranquilizer, antipsychotic, drugs fortreating Alzheimer's disease, antiparkinsonian agents, drugs fortreating amyotrophic lateral sclerosis, nerve nutritional factors,antidepressants, drugs for treating schizophrenia, anticancer drugs,Vitamin drugs, Vitamin derivatives, drugs for treating arthritis,antirheumatics, antiallergic drugs, antiasthmatic drugs, drugs fortreating atopic dermatitis, drugs for treating allergic rhinitis, drugsfor treating pollakiuria/involuntary micturition, proteolytic drugs,protease inhibitors, anti SIDS drugs, antisepsis drugs, anti septicshock drugs, endotoxin antagonists or antibodies, signal transductioninhibitors, inflammatory mediator action inhibitors, inflammatorymediator action inhibiting antibodies, inflammatory mediator productioninhibitors, antiinflammatory mediator action depressant,antiinflammatory mediator action inhibiting antibody, antiinflammatorymediator production inhibitor, al adrenergic agents, antiemetics, agentsfor preventing elevated methemoglobin, etc. Among these, anticancerdrugs, antibacterial agents, antifungal agents, nonsteroidalantiinflammatory drugs, steroid drugs, anticoagulants, antiemetics,agents for preventing elevated methemoglobin, etc. are preferred. Thefollowing comprise specific examples.

(1) Antibacterial Agents

(i) Sulfa drugs

Sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole,salazosulfapyridine, silver sulfadiazine, etc.

(ii) Quinoline antibacterial agents

Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleroxacin, etc.

(iii) Antitubercular agent

Isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylate(calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide,rifampicin, streptomycin sulphate, kanamycin sulfate, cycloserine, etc.

(iv) Acid fast bacterium drugs

Diaminodiphenylsulfone, rifampicillin, etc.

(v) Antiviral agents

Idoxuridine, acyclovir, vidarabine, ganciclovir, etc.

(vi) Anti HIV drugs

Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate,ritonavir, etc.

(vii) Anti-spirochetal drugs

(viii) Antibiotics

Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil,cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin,cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime,cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin,cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone,ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or saltsthereof, griseofulvin, Lankacidin species (J. Antibiotics, 38, 877-885(1985) and the like.(2) Antifungal Drugs(i) polyene antibiotics (for example, amphotericin B, nystatin,trichomycin)(ii) griseofulvin, pyrrolnitrin, etc.(iii) cytosine metabolism antagonists (for example, flucytosine)(iv) Imidazole derivatives (for example, econazole, clotrimazole,miconazole nitrate, bifonazole, croconazole)(v) triazole derivatives (for example, fluconazole, itraconazole, azolecompounds (2-((1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl)-4-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-3(2H,4H)−1,2,4-triazolone)(vi) thiocarbamic acid derivatives (for example, tolnaftate)(vii) Echinocandin derivatives (for example caspofungin, micafungin,anidulafungin).(3) Nonsteroidal Antiinflammatory Drugs

Acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, Migrenin,aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofensodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen,oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole,tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostatmesilate, ulinastatin, colchicine, probenecid, sulfinpyrazone,benzbromarone, allopurinol, sodium aurothiomalate, sodium hyaluronate,sodium salicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen,oxymorphone, meloxicam, celecoxib, rofecoxib and salts thereof, etc.

(4) Steroid Drugs

Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluocinonide, fluocinolone acetonide,prednisolone, methylprednisolone, cortisone acetate, hydrocortisone,fluorometholone, beclomethasone propionate, estriol, etc.

(5) Anticoagulants

Heparin sodium, sodium citrate, activated protein C, tissue factorpathway inhibitors, antithrombin III, dalteparin sodium, warfarinpotassium, argatroban, gabexate, sodium citrate, etc.

(6) Antiplatelet Drugs

Ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil,ticlopidine hydrochloride, pentoxifylline, dipyridamole, etc.

(7) Thrombolytic Drugs

Tisokinase, urokinase, streptokinase, etc.

(8) Immunomodulators

Cyclosporine, tacrolimus, gusperimus, azathioprine, antilymphocyteserum, dried sulfonated immunoglobulin, erythropoietin, colonystimulating factor, interleukin, interferon, etc.

(9) Antiprotozoal Drugs

Metronidazole, tinidazole, diethylcarbamazine citrate, quininehydrochloride, quinine sulfate, etc.

(10) Antitussive-Expectorant Drugs

Ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrinehydrochloride, methylephedrine hydrochloride, noscapine hydrochloride,alloclamide, chlorphedianol, picoperidamine, cloperastine, protokylol,isoproterenol, salbutamol, terbutalin, oxymetebanol, morphinehydrochloride, dextropethorphan hydrobromide, oxycodone hydrochloride,phosphoric acid dimorphan, tipepidine hibenzate, pentoxyverine citrate,clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, cysteine ethylester hydrochloride, carbocisteine, etc.

(11) Sedatives

Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital,amobarbital, pentobarbital, thiopental sodium, thiamylal sodium,nitrazepam, estazolam, flurazepam, haloxazolam, triazolam,flunitrazepam, bromvalerylurea, chloral hydrate, triclofos sodium, etc.

(12) Anesthetic Drugs

(12-1) Local Anesthetics

Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride,ethylaminobenzoic acid, oxethazaine and the like.

(12-2) General Anesthetics

(i) Inhalation anesthetics (for example, ether, halothane, nitrousoxide, influran, enflurane)

(ii) Intravenous anesthetics (for example, ketamine hydrochloride,droperidol, thiopental sodium, thiamylal sodium, pentobarbital) and thelike.

(13) Narcotic Antagonists

Levallorphan, nalorphine, naloxone and salts thereof, etc.

(14) Antiulcer Drugs

Metoclopromide, histidine hydrochloride, lansoprazole, metoclopramide,pirenzepine, cimetidine, ranitidine, famotidine, urogastrin,oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate,gefarnate, aldioxa, teprenone, prostaglandin, etc.

(15) Drugs for Treating Hyperlipidemia

HMG-Co Reductase inhibitors (for example, fluvastatin, cerivastatin,atorvastatin, etc.), fibrate system agents (for example, simfibrate,aluminum clofibrate, clinofibrate, fenofibrate, etc.), bile acidadsorbents (for example, cholestyramine, etc.), nicotinic acidpreparation (for example, nicomol, niceritrol, tocopherol nicotinate,etc.), probucol and derivatives thereof, polyunsaturated fatty acidderivative (for example, ethyl icosapentate, polyenephosphatidylcholine, melinamide, etc.), plant sterols (for example,yoryzanol, soy sterol, etc.), elastase, dextran sulfate sodium, squalenesynthase inhibitors, squalene epoxidase inhibitors, CETP inhibitors,2-chloro-3-(4-(2-methyl-2-phenyl propoxy) phenyl) propionic acid ethylester (Chem, Pharm. Bull), 38, 2792-2796 (1990), LDL receptor enhancer,cholesterol absorption inhibitors (Ezetimibe, etc.), MTP inhibitors,ileal bile acid transporter inhibitors, SCAP ligand, FXR ligands, etc.

(16) Drugs for Treating Arteriosclerosis

MMP inhibitors, chymase inhibitors, ACAT inhibitors (Avasimibe,Eflucimibe, etc.), apoAI Milano and analogue thereof, scavenger receptorinhibitors, 15-lipoxygenase inhibitors, phospholipase A2 inhibitors,ABCA1 activator, LXR ligand, sphingomyelinase inhibitors, paraoxonaseactivator, estrogen receptor agonists, etc.

(17) HDL-Elevating Drugs

Squalene synthase inhibitors, CETP inhibitors, LPL activators, etc.

(18) Unstable Plaque Stabilizing Drugs

MMP inhibitors, chymase inhibitors, ACAT inhibitors, lipid rich plaqueretraction agents, etc.

(19) Myocardial Protective Agents

Oral agents for cardiac ATP-K, endothelin antagonists, urotensinantagonists, etc.

(20) Drugs for Treating Hypothyroidism

Desicated thyroid (Chireoido), sodium levothyroxine (Thyradin-S),liothyronine sodium (thyronine, thyromine) and the like.

(21) Drugs for Treating Nephrotic Syndrome

Prednisolone (predonine), prednisolone sodium succinate (predonine),methylprednisolone sodium succinate (Solu-Medrol), betamethasone(Rinderon), and the like.

(22) Agents for Treating Chronic Renal Failure

Diuretics (for example, furosemide (Lasix), bumetanide (Lunetoron),azosemide (Diart)). Antihypertensive agents (for example, ACEinhibitors, enalapril maleate (Renivace), calcium antagonists(manidipine), α receptor blockers, AII antagonists (Candesartan)) andthe like.

(23) Diuretics

Thiazide derivative diuretics (benzylhydrochlorothiazide,cyclopenthiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide,methylclothiazide, penfluthiazide, polythiazide, trichlormethiazide,etc.), loop diuretics (chlorthalidone, clofenamide, indapamide,mefruside, meticrane, sotolazone, tripamide, quinethazone, metolazone,furosemide, etc.), potassium sparing diuretics (spironolactone,triamterene, etc.).

(24) Antihypertensive Drugs

(i) Sympatholytic agents

α2 agonist (for example, clonidine, guanabenz, guanfacine, methyldopa,etc.), gangliolytic (for example, hexamethonium, trimethaphan, etc.),presynaptic blockers (for example, alseroxylon, dimethylaminoreserpinate, rescinnamine, reserpine, syrosingopine, etc.), neuronblockers (for example, betanidine, guanethidine, etc.), α1 blockers (forexample, bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.), βblockers (for example, propranolol, nadolol, timolol, nipradilol,bunitrolol, indenolol, penbutolol, carteolol, carvedilol, pindolol,acebutolol, atenolol, bisoprolol, metoprolol, labetalol, amosulalol,arotinolol, etc.) and the like.

(ii) Vasodilators

Calcium channel antagonists (for example, manidipine, nicardipine,nilvadipine, nisoldipine, nitrendipine, benidipine, amlodipine,aranidipine, etc.), phthalazines (for example, budralazine, cadralazine,ecarazine, hydralazine, todralazine, etc.) and the like.

(iii) ACE inhibitors

Alacepril, captopril, cilazapril, delapril, enalapril, lisinopril,temocapril, trandolapril, quinapril, imidapril, benazepril, perindopril,etc.

(iv) AII antagonists

Losartan, Candesartan, valsartan, Telmisartan, Irbesartan, forasartan,etc.

(v) Diuretics

(for example, said diuretics, etc.).

(25) Drugs for Treating Cardiac Failure

Cardiotonics (for example, digitoxin, digoxin, methyldigoxin, lanatosideC, proscillaridin, etc.), α,β agonists (for example, epinephrine,norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine,denopamine, etc.), phosphodiesterase inhibitors (for example, amrinone,milrinone, olprinone hydrochloride, etc.) calcium channel sensitizers(for example, pimobendan, etc.), nitrovasodilators (for example,nitroglycerin, isosorbide dinitrate, etc.), ACE inhibitors (for example,said ACE inhibitor, etc.), diuretics (for example, said diuretic, etc.),carperitide, ubidecarenone, vesnarinone, aminophylline, etc.

(26) Muscle Relaxants

Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlorzoxazone, eperisone, tizanidine, etc.

(27) Antiepileptic Drugs

Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sultiame, sodium valproate,clonazepam, diazepam, nitrazepam, etc.

(28) Cardiotonics

aminophylline, etilefrine, dopamine, dobutamine, denopamine,aminophylline, amrinone, pimobendane, ubidecarenone, digitoxin, digoxin,methyldigoxin, lanatoside C, G-strophanthin, etc.

(29) Vasodilators

Oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz, etc.

(30) Vasoconstrictors

Dopamine, dobutamine denopamine, etc.

(31) Drugs for Treating Arrhythmia

(i) Sodium channel blockers (for example, quinidine, procainamide,disopyramide, ajmaline, cibenzoline, lidocaine, diphenylhydantoin,mexiletine, propafenone, flecainide, pilsicainide, phenytoin, etc.)

(ii) β blockers (for example, propranolol, alprenolol, bufetolol,oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol,carteolol, arotinolol, etc.)

(iii) Potassium channel blockers (for example, amiodarone, etc.)

(iv) Calcium channel blockers (for example, verapamil, diltiazem, etc.),and the like.

(32) Vasopressors

Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-strophanthin, etc.

(33) Drugs for Treating Diabetic Mellitus

Sulfonylurea agents (for example, tolbutamide, chlorpropamide,glyclopyramide, acetohexamide, tolazamide, glibenclamide, glybuzole,etc.), biguanide agents (for example, metformin hydrochloride, bulforminhydrochloride, etc.), α-glucosidase inhibitors (for example, Voglibose,acarbose, etc.), insulin sensitizers (for example, pioglitazone,roziglitazone, troglitazone, etc.), insulin, glucagon, agents fortreating diabetes complications (for example, epalrestat, etc.), DPP4inhibitors (for example, sitagliptin, vildagliptin, Alogliptin,linagliptin, etc.) and the like.

(34) Tranquilizers

Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine,etc.

(35) Antipsychotics

Chlorpromazine hydrochloride, prochlorperazine, trifluoperazine,thioridazine hydrochloride, perphenazine maleate, fluphenazineenanthate, prochlorperazine maleate, levomepromazine maleate,promethazine hydrochloride, haloperidol, bromperidol, spiperone,reserpine, clocapramine hydrochloride, sulpiride, zotepine, etc.

(36) Drug for Treating Alzheimer's Diseases

(i) Cholinesterase inhibitors such as donepezil, rivastigmine,galantamine, etc.

(ii) Cerebral function activators, etc. such as idebenone, memantine,vinpocetine, etc.

(37) Antiparkinsonian Agents

L-DOPA, deprenyl, carbidopa+levodopa, pergolide, ropinirole,cabergoline, pramipexole, entacapone, lazabemide, etc.

(38) Drugs for Treating Amyotrophic Lateral Sclerosis

Riluzole, mecasermin, gabapentin, etc.

(39) Antidepressants

Imipramine, clomipramine, noxiptiline, phenelzine, amitriptylinehydrochloride, nortriptyline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluvoxaminemaleate, trazodone hydrochloride, etc.

(40) Drugs for Treating Schizophrenia

Olanzapine, risperidone, quetiapine, iloperidone, etc.

(41) Anticancer Drugs

6-O—(N-chloroacetylcarbamoyl)fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,Picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulphate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine,mercaptopurine, tegafur, carmofur, cytarabine, methyl testosterone,testosterone propionate, testosterone enanthate, mepitiostane,fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelinacetate, paclitaxel, docetaxel, oxaliplatin, vincristine, vinblastine,cisplatin, carboplatin, bortezomib, etc.

(42) Vitamin Drugs

(i) Vitamin A types: Vitamin A₁, Vitamin A₂ and retinol palmitate

(ii) Vitamin D types: Vitamin D₁, D₂, D₃, D₄ and D₅

(iii) Vitamin E types: α-tocopherol, β-tocopherol, γ-tocopherol,δ-tocopherol, nicotinic acid dl-α-tocopherols

(iv) Vitamin K types: Vitamin K₁, K₂, K₃ and K₄

(v) Folic acid (Vitamin M)

(vi) Vitamin B types: Vitamin B₁, Vitamin B₂, Vitamin B₃, Vitamin B₅,Vitamin B₆ and Vitamin B₁₂

(vii) Biotin (Vitamin H), etc.

(43) Vitamin Derivatives

Various vitamin derivatives such as, for example, ascorbic acid, VitaminD₃ derivatives such as 5, 6-trans-cholecalciferol, 2,5-hydroxycholecalciferol and 1-α-hydroxycholecalciferol, etc., VitaminD₂ derivatives such as 5, 6-trans-ergocalciferol, etc., etc.

(44) Antiallergic Drugs

Diphenhydramine, chlorpheniramine, tripelennamine, clemizole,diphenylpyraline, methoxyphenamine, disodium cromoglycate, tranilast,repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine,azelastine, epinastine, ozagrel hydrochloride, Pranlukast hydrate,seratrodast, etc.

(45) Antiasthmatic Drugs

Isoprenaline hydrochloride, salbutamol sulphate, procaterolhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tulobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropiumbromide, flutropium bromide, theophylline, aminophylline, disodiumcromoglycate, tranilast, repirinast, ibudilast, ketotifen, terfenadine,mequitazine, azelastine, epinastine, ozagrel hydrochloride, Pranlukasthydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone,beclomethasone proprionate, etc.

(46) Drugs for Treating Atopic Dermatitis

Disodium cromoglycate, etc.

(47) Drugs for Treating Allergic Rhinitis

Disodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate,clemastine fumarate, homochlorcyclizine hydrochloride, terfenadine,mequitazine, etc.

(48) Drugs for Treating Pollakiuria/Involuntary Micturition

Flavoxate hydrochloride, etc.

(49) Antisepsis Drugs

Peptide compounds such rBPI-21 (bactericidal permeability increasingprotein), BI-51017 (antithrombin III), SC-59735(rTFPI), r-PAFacetylhydrolase, LY-203638 (r-activated protein C), anti TNF-α antibody,anti CD14 antibody, CytoFab, alkaline phosphatase (LPS inactivator),etc., non-peptide compounds such as JTE-607, eritoran, S-5920,FR-167653, ONO-1714, ONO-5046 (sivelestat), GW-273629, RWJ-67657,GR-270773, NOX-100, GR-270773, NOX-100, INO-1001, etc. and the like.

(50) Drugs for Improving Prognosis after Coronary Artery Bypass Surgery

Eritoran, etc.

(51) Antiemetics

Phenothiazine derivatives, 5-HT3 receptor antagonists, etc.

(52) Agents for Preventing Elevated Methemoglobin

Methylene blue, ascorbic acid, etc.

(53) Anticytokine Agents

(I) Protein preparations

(i) TNF inhibitors

Etanercept, Infliximab, adalimubab, certolizumab pegol, golimumab,PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti TNF-αantibody, etc.

(ii) Interleukin-1 inhibitors

Anakinra (interleukin-1 receptor antagonists), soluble interleukin-1receptor, etc.

(iii) Interleukin-6 inhibitors

Tocilizumab (anti interleukin-6 receptor antibody), anti interleukin-6antibody, etc.

(iv) Interleukin-10 drugs

Interleukin-10, etc.

(v) Interleukin-12/23 inhibitors

Ustekinumab, briakinumab (anti interleukin-12/23 antibody), etc.

(vi) interleukin-17 inhibitors

Secukinumab, ixekizumab, brodalumab, etc.

(II) Non-protein preparations

(i) MAPK inhibitors

BMS-582949, etc.

(ii) Gene control drugs

Inhibitors of molecules related to signal transductions such as NFκK,NF-κB, IKK-1, IKK-2, AP-1, etc.

(iii) Cytokine production inhibitors

Iguratimod, tetomilast, etc.

(iv) TNF-α converting enzyme inhibitors

(v) Interleukin-1 β converting enzyme inhibitors

VX-765, etc.

(vi) Interleukin-6 antagonists

HMPL-004, etc.

(vii) Interleukin-8 inhibitors

IL-8 antagonists, CXCR1 & CXCR2 antagonists, cefalexin, etc.

(viii) chemokine antagonists

CCR9 antagonists (CCX-282, CCX-O25), MCP-1 antagonists, etc.

(ix) Interleukin-2 receptor antagonists

Denileukin, diftitox, etc.

(x) Therapeutic vaccines

TNF-α vaccine, etc.

(xi) Gene therapy drugs

Gene therapy drugs having the object of elevating expression of geneshaving antiinflammatory effect such as interleukin-4, interleukin-10,soluble interleukin-1 receptor, soluble TNF-α receptor, etc.

(xii) Antisense compounds

ISIS-104838, etc.

(54) Integrin Inhibitors

Natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.

Antidepressant drugs (for example, amitriptyline, imipramine,clomipramine, desipramine, doxepin, nortriptyline, duloxetine,milnacipran, fluoxetine, paroxetine, sertraline, citalopram, etc.)Anticonvulsants drugs (for example, carbamazepine, pregabalin,gabapentin, lamotrigine, phenytoin, valproic acid, etc.)

Narcotics (for example, morphine, oxycodone, fentanyl, methadone,codeine, tramadol, etc.).

(55) Others

Hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins,etc.

During combined use, the times of administration of the compound of thepresent invention and the co-used drug are not restricted, and compoundsof the present invention and co-used drug may be administered at thesame or different times with respect to an administration subject. Ifthe dose of the co-used drug is in accordance with the dose usedclinically, then the co-used dose can be suitably selected depending onthe administration subject, administration route, disease andcombination.

The form of the administration of the combination is not restricted inparticular, and the compound of the present invention and co-used drugmay be combined during administration. As such form of administration,for example, (1) administration of single pharmaceutical preparationobtained by formulating the compound of the present invention and aco-used drug at the same time, (2) administration at the same time andby the same administration route of two kinds of pharmaceuticalpreparations in which the compound of the present invention and theco-used drug are separately formulated, (3) administration at differenttimes but by the same administration route of two kinds ofpharmaceutical preparations in which the compound of the presentinvention and the co-used drug are separately formulated, (4)administration at the same time but by different administration routesof two kinds of pharmaceutical preparations in which the compound of thepresent invention and the co-used drug are separately formulated, and(5) administration at different times and by different administrationroutes of two kinds of pharmaceutical preparations in which the compoundof the present invention and the co-used drug are separately formulated,(for example, administration of co-used drug after having administeredthe compound of the present invention or administration in the reverseorder to this), may be proposed.

The compounding ratio of the compound of the present invention andco-used drug in the combined use agent of the present invention can besuitably selected depending on the administration subject, theadministration route, the disease, etc.

For example, the content of the compound of the present invention in thecombined use agent of the present invention, differs depending on theform of the preparation, however, said content is usually about 0.01 to100 wt. %, preferably about 0.1 to 50 wt. %, and more preferably about0.5 to 20 wt. % with respect to the whole pharmaceutical preparation.

The content of co-used drug in the combined use agent of the presentinvention, differs depending on the form of the preparation, however,said content is usually about 0.01 to 100 wt. %, preferably about 0.1 to50 wt. %, and more preferably about 0.5 to 20 wt. % with respect to thewhole pharmaceutical preparation.

The content of additive such as carrier, etc. in the combined use agentof the present invention, differs depending on the form of thepreparation, however said content is usually about 1 to 99.99 wt. %,preferably about 10 to 90 wt. % with respect to the whole pharmaceuticalpreparation. Moreover, the compound of the present invention and co-useddrug may be contained in similar contents when each are respectivelyformulated pharmaceutically separately.

The dose differs depending on the type of the compound of the presentinvention, the administration route, the symptoms and the age ofpatient, etc., and, for example, when compound (I) is orallyadministered to a patient (about 60 kg in weight) withchemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-inducedneuropathic pain (CINP), liver injury and/or ischemia-reperfusion injury(IRI), about 0.1 mg/kg body weight to about 30 mg/kg body weight,preferably about 1 mg/kg to 20 mg/kg in weight body weight areadministered per day, either in one administrative dose or dividedseveral times.

The dose when the drug of the present invention is a slow releasepreparation varies depending on the kind and the content of compound(I), the agent form, the duration of the drug release, the administeredsubject animal (for example, mammalian organism such as mouse, rat,hamster, guinea pig, rabbit, cat, dog, cow, horse, pig, sheep, monkey,human, etc.) and the purpose of the administration, but for example whenapplied by parenteral administration, about 0.1 to 100 mg of compound(I) should be released from the administered pharmaceutical preparationover a week.

The co-used drug can be established in an amount within a range withwhich adverse reactions are not a problem. The daily dose of the co-useddrug varies depending on the severity of the symptoms, the age, gender,body weight and sensitivity of the administration subject, the durationof administration, the interval, the properties, compound and kind ofdrug preparation and the type of active ingredient; and is not limitedin particular, however, usually the dose of drug by oral administrationis about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, morepreferably about 0.1 to 100 mg per 1 kg body weight of mammalianorganism; divided by 1 to 4 times per day. When a co-used drug of thepresent invention is administered, the compound of the present inventionand co-used drug may be administered over the same time periods, or maybe administered over different time periods. When administered overdifferent periods, the time difference varies depending on theadministered active ingredient, formulation and administration method,however, for example, when the co-used drug is administered first, amethod may be adopted wherein the compound of the present invention isadministered within 1 minute to 3 days, preferably within 10 minutes to1 day, more preferably still 15 minutes to 1 hour, after administrationof the co-used drug. When the compound of the present invention isadministered first, a method may be adopted wherein the co-used drug isadministered within 1 minute to 1 day, preferably 10 minutes to 6 hours,more preferably 15 minutes to 1 hour, after the administration of thecompound of the present invention.

EXAMPLES

The present invention will now be described in detail by reference tothe following Examples, Test Examples and Preparation Examples, but theinvention is in no way limited by these, and moreover changes may bemade thereto within a range that do not deviate from the scope of thepresent invention.

In the following Examples, “room temperature” usually denotes about 10°C. to about 35° C. The ratios shown for mixed solvents denote the ratiosby volume, unless otherwise stated in particular. % denotes wt. % unlessotherwise stated in particular.

In HPLC (high performance liquid chromatography), a description of C18,denotes that octadecyl-bonded silica gel was used. The ratios for theeluting solvents denote the ratios by volume unless otherwise stated inparticular.

The following abbreviations are used in the following Examples.

mp: Melting point

MS: Mass spectrum

[M+H]⁺ (M−H)⁻: Molecular ion peaks

M: Molar concentration

N: Normal

CDCl₃: Deuterated chloroform

DMSO-d₆: Deuterated dimethyl sulfoxide

¹H NMR: Proton nuclear magnetic resonance

LC/MS: Liquid chromatograph mass spectrometer

ESI: Electrospray Ionization

APCI: Atmospheric Pressure Chemical Ionization

SFC: Supercritical fluid chromatography

THF: Tetrahydrofuran

DME: 1,2-dimethoxyethane

IPE: Diisopropyl ether

DMF: N,N-dimethylformamide

DMA: N,N-dimethylacetamide

NMP: N-methyl-2-pyrrolidone

DMSO: Dimethyl sulfoxide

CPBA: m-Chloroperbenzoic acid

TMSOTf: Trimethylsilyl triflate

DBU: 1,8-diazabicyclo[5.4.0]-7-undecene.

¹H NMR was measured with a Fourier transform NMR. ACD/SpecManager (brandname) etc., was used for the analysis. No description is provided forthe extremely slight peaks of the protons of, for example, hydroxygroups and amino groups, etc.

The MS was measured using an LC/MS. The ionization method used was anESI method or APCI method. The data described is the actual values(found). Usually the molecular ion peaks are seen, but when a compoundhas a t-butoxycarbonyl group, a peak after elimination of atert-butoxycarbonyl group or tert-butyl group may be observed as afragment ion. Moreover, in the case of a compound having a hydroxygroup, a peak after the elimination of H₂O may be observed. In the caseof a salt, usually a fragment ion peak or the molecular ion peak of thecompound is observed. In the optical rotation ((α)_(D)), the unit of thesample concentration (c) is g/100 mL.

For the elemental analysis values (Anal), theoretical values (Calcd) andthe actual values (Found) are provided.

Example 1 Ethyl6-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)cyclohex-1-ene-1-carboxylate(a mixture of 4 stereoisomers)

Step A

Sodium borohydride (1.7 g) was added with ice cooling to an ethanolsolution (60 mL) of 4-chloroindan-1-one (5.0 g) and the mixture wasstirred at room temperature for one hour. About half of the solvent waseliminated by distillation under reduced pressure, and water was addedto the residue and extraction performed with ethyl acetate. The liquidextract was washed with saturated aqueous sodium chloride solution andwas dried with sodium sulfate, and the solvent was eliminated bydistillation under reduced pressure, and 4-chloroindan-1-ol (5.0 g) wasobtained as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 1.77 (1H, d, J=7.2 Hz), 1.91-2.03 (1H, m),2.47-2.59 (1H, m), 2.79-2.90 (1H, m), 3.05-3.16 (1H, m), 5.25-5.32 (1H,m), 7.17-7.33 (3H, m).

Step B

Phosphorous tribromide (2.8 mL) was added at 0° C. to a diethyl ethersolution (70 mL) of 4-chloroindan-1-ol (5.0 g) and the mixture wasstirred at the same temperature for four hours. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure, and1-bromo-4-chloroindane (6.83 g) was obtained as a colorless oilysubstance.

¹H NMR (300 MHz, CDCl₃) δ 2.47-2.72 (2H, m), 2.92-3.05 (1H, m),3.11-3.26 (1H, m), 5.57 (1H, dd, J=6.2, 2.5 Hz), 7.15-7.26 (2H, m), 7.31(1H, d, J=7.6 Hz).

Step C

Potassium carbonate (7.74 g) was added at room temperature to a mixtureof glutaraldehyde (5.6 M aqueous solution, 150 mL) and ethyl(diethoxyphosphoryl)acetate (115 mL), and the mixture was stirred at thesame temperature for one hour. An aqueous solution (300 mL) of potassiumcarbonate (116 g) was added to the reaction mixture, and it was stirredovernight at the same temperature. Sodium chloride (100 g) was added tothe reaction mixture and extraction was performed with ethyl acetate.The liquid extract was concentrated, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) and ethyl6-hydroxycyclohex-1-ene-1-carboxylate (54.6 g) was obtained as acolorless oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.29-1.34 (3H, m), 1.54-1.62 (1H, m),1.71-1.85 (3H, m), 2.10-2.30 (2H, m), 3.13 (1H, d, J=2.6 Hz), 4.24 (2H,q, J=6.9 Hz), 4.54 (1H, brs), 7.10 (1H, t, J=4.0 Hz).

Step D

N,N-dimethyl-4-aminopyridine (3.88 g) and acetic anhydride (90 mL) weresuccessively added at room temperature to a pyridine solution (350 mL)of ethyl 6-hydroxycyclohex-1-ene-1-carboxylate (54.0 g), and the mixturewas stirred at the same temperature for one hour. The reaction mixturewas diluted with saturated aqueous sodium bicarbonate solution andextraction was performed with ethyl acetate. The liquid extract waswashed with saturated aqueous sodium bicarbonate solution and saturatedaqueous sodium chloride solution and was dried with magnesium sulfate,and the solvent was eliminated by distillation under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl 6-acetoxycyclohex-1-ene-1-carboxylate (42.0 g)was obtained as a colorless oily substance.

MS: [M+H]⁺ 213.2.

Step E

Triethylamine (30.3 mL) and potassium thioacetate (27.1 g) weresuccessively added at room temperature to an ethanol solution (320 mL)of ethyl 6-acetoxycyclohex-1-ene-1-carboxylate (42.0 g), and the mixturestirred overnight at the same temperature. The reaction mixture wasconcentrated under reduced pressure, and water was added to the residueand extraction was performed with ethyl acetate. The liquid extract waswashed with saturated aqueous sodium chloride solution and was driedwith sodium sulfate, and the solvent was eliminated by distillationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and ethyl6-(acetylsulfanyl)cyclohex-1-ene-1-carboxylate (37.1 g) was obtained asa colorless oily substance.

MS: [M+H]⁺ 229.2.

Step F

4N hydrochloric acid (ethyl acetate solution, 203 mL) was added at roomtemperature to an ethanol solution (200 mL) of ethyl6-(acetylsulfanyl)cyclohex-1-ene-1-carboxylate (37.0 g) and the mixturewas stirred overnight at 50° C. The reaction mixture was concentratedunder reduced pressure, and saturated aqueous sodium bicarbonatesolution was added to the residue and extraction was performed withethyl acetate. The liquid extract was washed with water and saturatedaqueous sodium chloride solution and was dried with sodium sulfate, andthe solvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl 6-sulfanylcyclohex-1-ene-1-carboxylate (21.0g) was obtained as a colorless oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.31 (3H, t, J=7.0 Hz), 1.66-1.75 (1H, m),1.85-1.97 (3H, m), 2.11 (1H, d, J=6.8 Hz), 2.14-2.38 (2H, m), 4.01-4.08(1H, m), 4.18-4.28 (2H, m), 6.92-6.96 (1H, m).

Step G

DBU (0.18 mL) was added with ice cooling to a mixture of ethyl6-sulfanylcyclohex-1-ene-1-carboxylate (200 mg), 1-bromo-4-chloroindane(249 mg) and DMF (4 mL), and the mixture was stirred at the sametemperature for 20 minutes. The reaction mixture was diluted with waterand extracted with ethyl acetate. The liquid extract was washed withwater and saturated aqueous sodium chloride solution and was dried withmagnesium sulfate, and the solvent was eliminated by distillation underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and ethyl6-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)cyclohex-1-ene-1-carboxylate(a mixture of 4 stereoisomers) (338 mg) was obtained as a colorless oilysubstance.

¹H NMR (300 MHz, CDCl₃) δ 1.28-1.34 (3H, m), 1.68-1.85 (2H, m),1.88-2.04 (2H, m), 2.13-2.30 (2H, m), 2.30-2.45 (1H, m), 2.51-2.67 (1H,m), 2.87-2.98 (1H, m), 3.08-3.20 (1H, m), 3.97 (1H, d, J=14.4 Hz),4.17-4.27 (2H, m), 4.50-4.60 (1H, m), 6.94-6.99 (1H, m), 7.09-7.21 (2H,m), 7.23-7.33 (1H, m).

Step H

mCPBA (4.14 g, 72%) was added with ice cooling to a mixture of ethyl6-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)cyclohex-1-ene-1-carboxylate(a mixture of 4 stereoisomers) (338 mg) and acetonitrile (4 mL), and themixture was stirred at room temperature for one hour. The reactionmixture was diluted with saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The liquid extract was washed withaqueous sodium chloride solution and was dried with magnesium sulfate,and the solvent was eliminated by distillation under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl6-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)cyclohex-1-ene-1-carboxylate(a mixture of 4 stereoisomers) (342 mg) was obtained as a colorless oilysubstance.

¹H NMR (300 MHz, CDCl₃) δ 1.30-1.40 (3H, m), 1.53-1.79 (2H, m),1.94-2.15 (1H, m), 2.17-2.32 (1H, m), 2.35-2.52 (2.5H, m), 2.58-2.75(1H, m), 2.86-3.09 (1.5H, m), 3.21-3.36 (1H, m), 4.22-4.31 (2H, m),4.36-4.41 (0.5H, m), 4.59-4.64 (0.5H, m), 4.86-4.92 (1H, m), 7.15-7.24(1H, m), 7.28-7.32 (1H, m), 7.38-7.45 (1H, m), 7.48 (0.5H, d, J=7.6 Hz),7.62 (0.5H, d, J=7.6 Hz).

Example 2 Ethyl(2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers)

Step A

Sodium borohydride (52.5 g) was added with ice cooling to a methanolsolution (1000 mL) of dimethyl(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (87 mL) and themixture was stirred at the same temperature for one hour and at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and then diluted with saturated aqueous sodiumchloride solution and stirred at room temperature for one hour, and thenextracted eight times with ethyl acetate. The liquid extracts werecombined and dried with sodium sulfate, and the solvent was eliminatedby distillation under reduced pressure((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (64.8 g) wasobtained as a straw-colored oily substance.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (6H, s), 3.40-3.58 (4H, m), 3.67-3.82(2H, m), 4.81 (2H, t, J=5.7 Hz).

Step B

Amberlyst 15 hydrogen form (4.8 g, purchased from SIGMA-ALDRICH) wasadded at room temperature to a mixture of((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (86 g), methanol(121 mL) and water (1205 mL), and the mixture was stirred overnight at60° C. The solids were eliminated by filtration, and the filtrate wasconcentrated under reduced pressure. Ethanol was added to the residue,and the mixture was concentrated to dryness. The obtained solids werebrayed with mortar, and washed with liquid mixture of hexane/IPE=1/1,and (2R,3R)-butane-1,2,3,4-tetraol (51.7 g) was obtained.

¹H NMR (300 MHz, DMSO-d₆) δ 2.48-2.53 (2H, m), 3.28-3.43 (4H, m), 4.22(2H, d, J=5.7 Hz), 4.35-4.48 (2H, m).

Step C

Benzoyl chloride (103 mL) was added at room temperature to NMP solution(1000 mL) of (2R,3R)-butane-1,2,3,4-tetraol (51.7 g) and the mixture wasstirred at 50° C. for two hours. Water (1500 mL) was added to thereaction mixture and the solids formed were recovered by filtration andwashed with water. The obtained solids were dissolved in ethyl acetateand washed with water and saturated aqueous sodium chloride solution anddried with magnesium sulfate. The solvent was eliminated by distillationunder reduced pressure, and the obtained solids were recrystallized fromethyl acetate/hexane, and (2R,3R)-2,3-dihydroxybutane-1,4-diyldibenzoate (77.3 g) was obtained.

MS. found: 353.0.

Step D

Chlorotrimethylsilane (62.8 mL) was added with ice cooling to a mixtureof (2R,3R)-2,3-dihydroxybutane-1,4-diyl dibenzoate (77.3 g),N,N-dimethyl-4-aminopyridine (2.86 g), triethylamine (71.8 mL) and DMF(780 mL), and the mixture was stirred at the same temperature for onehour. The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The liquidextract was washed with water and saturated aqueous sodium chloridesolution and was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The obtained solidswere washed with hexane, and(2R,3R)-2,3-bis((trimethylsilyl)oxy)butane-1,4-diyl dibenzoate (105 g)was obtained.

MS. found: 475.2.

Step E

A THF solution (300 mL) of 1,4-dioxaspiro[4.5]decan-8-one (100 g) wasadded while heating under reflux to a mixture of diethyl carbonate (189g), potassium t-butoxide (216 g) and THF (900 mL), and the mixture wasstirred at the same temperature for five hours. The solids recovered byfiltration were washed with ethyl acetate and dissolved in water (100mL), and then added to a liquid mixture of water (50 mL) and acetic acid(50 mL) while ice cooling, and then extracted three times with ethylacetate. The liquid extracts were combined and washed with water(twice), saturated aqueous sodium bicarbonate solution and saturatedaqueous sodium chloride solution and dried with magnesium sulfate andfiltered using silica gel. The filtrate was concentrated under reducedpressure, and ethyl 8-hydroxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(101 g) was obtained as an oily substance.

¹H NMR (300 MHz, DMSO-d₆) δ 1.13-1.21 (3H, m), 1.76 (2H, t, J=6.6 Hz),2.33-2.42 (4H, m), 3.86-3.99 (6H, m), 12.14 (1H, s).

Step F

Trifluoromethanesulfonic anhydride (124 mL) was added at −78° C. to amixture of ethyl 8-hydroxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(115 g), N-ethyl-N-(1-methylethyl) propan-2-amine (106 mL) and toluene(1008 mL), and the mixture was stirred at the same temperature for onehour. The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and was stirred at room temperature for 30 minutes,and thereafter, about half of the organic solvent was eliminated bydistillation under reduced pressure, and the obtained mixture wasextracted twice with ethyl acetate. The liquid extracts were combinedand washed with water and saturated aqueous sodium chloride solution anddried with magnesium sulfate, and the solvent was eliminated bydistillation under reduced pressure, and ethyl8-(((trifluoromethyl)sulfonyl)oxy)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(181 g) was obtained.

MS: [M+H]⁺ 361.0.

Step G

Potassium thioacetate (91 g) was added at room temperature to a DMSO(500 mL) solution of ethyl8-(((trifluoromethyl)sulfonyl)oxy)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(144 g) and the mixture was stirred at the same temperature for sixhours. The reaction mixture was diluted with water and extracted withethyl acetate. The liquid extract was washed with water and saturatedaqueous sodium chloride solution and was dried with magnesium sulfate,and the solvent was eliminated by distillation under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl8-(acetylsulfanyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate (71.8 g)was obtained as a straw-colored oily substance.

MS. found: 309.0.

Step H

4N hydrochloric acid (ethyl acetate solution, 345 mL) was added with icecooling to a THF (500 mL) solution of ethyl8-(acetylsulfanyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate (79.1 g)and the mixture was stirred at room temperature for six hours, and thenfurther 4N hydrochloric acid (ethyl acetate solution, 1036 mL) wasadded, and the mixture was stirred overnight at room temperature. Thereaction mixture was concentrated down under reduced pressure to avolume of about 500 mL, and then diluted with water, and extraction wasperformed with ethyl acetate. The liquid extract was washed with water,saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl6-(acetylsulfanyl)-3-oxocyclohex-1-ene-1-carboxylate (59.1 g) wasobtained as a straw-colored oily substance.

MS=(M−H)⁻ 241.0.

Step I

Pyridinium p-toluenesulfonate (20.2 g) was added with ice cooling to amixture of ethyl 6-(acetylsulfanyl)-3-oxocyclohex-1-ene-1-carboxylate(18.5 g), trimethoxymethane (40.5 g) and methanol (382 mL), and themixture was stirred at room temperature for six hours. The reactionmixture was diluted with saturated aqueous sodium bicarbonate solution,and the organic solvent was eliminated by distillation under reducedpressure. The residue was extracted twice with ethyl acetate, and theextracts were combined and washed with water and saturated aqueoussodium chloride solution and was dried with sodium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Aprocedure wherein toluene was added to the residue and then eliminatedby distillation under vacuum, was repeated several times, and ethyl6-(acetylsulfanyl)-3,3-dimethoxycyclohex-1-ene-1-carboxylate (22.6 g)was thereby obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (3H, t, J=7.0 Hz), 1.70-1.83 (1H, m),1.84-1.96 (1H, m), 1.98-2.08 (1H, m), 2.12-2.28 (1H, m), 2.32 (3H, s),3.25 (3H, s), 3.30 (3H, s), 4.15-4.26 (2H, m), 4.63-4.70 (1H, m),6.81-7.03 (1H, m).

Step J

TMSOTf (755 μL) was added with ice cooling to a mixture of ethyl6-(acetylsulfanyl)-3,3-dimethoxycyclohex-1-ene-1-carboxylate (24 g),(2R,3R)-2,3-bis((trimethylsilyl)oxy)butane-1,4-diyl dibenzoate (39.5 g)and acetonitrile (550 mL), and the mixture was stirred at the sametemperature for one hour. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane). The obtained solids were washedwith hexane and ethyl(2R,3R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (41.5 g) was obtained.

MS. found: 577.1.

Step K

Potassium carbonate (86 mg) was added with ice cooling to a mixture ofethyl(2R,3R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (115 mg), 1-bromo-4-chloroindane (48 mg)and methanol (4 mL), and the mixture was stirred at room temperature forthree hours. The reaction mixture was diluted with 1N hydrochloric acidand extraction was performed with ethyl acetate/THF liquid mixture. Theliquid extract was washed with saturated aqueous sodium chloridesolution and was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (62.0 mg) was obtained as a colorlessoily substance.

MS. found: 477.4.

Step L

mCPBA (66.7 mg, 74%) was added with ice cooling to an acetonitrilesolution (2 mL) of ethyl(2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (62.0 mg) and the mixture was stirred atroom temperature for two hours. The reaction mixture was diluted withwater and extracted with ethyl acetate. The liquid extract was washedwith saturated aqueous sodium chloride solution and was dried withmagnesium sulfate, and the solvent was eliminated by distillation underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and ethyl(2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (57 mg) was obtained.

¹H NMR (400 MHz, CDCl₃) δ 1.30-1.41 (3H, m), 1.83-1.95 (1H, m),2.07-2.15 (1H, m), 2.27-2.51 (3.5H, m), 2.59-2.71 (1H, m), 2.84-2.93(0.5H, m), 2.96-3.11 (1H, m), 3.20-3.33 (1H, m), 3.68-3.77 (2H, m),3.78-3.91 (2H, m), 3.98-4.04 (0.5H, m), 4.07-4.36 (5H, m), 4.55-4.60(0.5H, m), 4.84-4.93 (1H, m), 6.92-6.97 (0.5H, m), 6.99-7.04 (0.5H, m),7.16-7.23 (1H, m), 7.29-7.34 (1H, m), 7.45-7.50 (0.5H, m), 7.52-7.59(0.5H, m).

Example 3 Ethyl(2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers)

Step A

Amberlyst 15 hydrogen form (1.0 g, purchased from SIGMA-ALDRICH) wasadded at room temperature to the mixture of((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (30.0 g),methanol (28 mL) and water (280 mL), and the mixture was stirredovernight at 60° C. The solids were eliminated by filtration, and thefiltrate was concentrated under reduced pressure. The obtained solidswere washed with hexane, and (2S,3S)-butane-1,2,3,4-tetraol (22.1 g) wasobtained.

¹H NMR (300 MHz, DMSO-d₆) δ 3.32-3.48 (6H, m), 4.21 (2H, d, J=5.3 Hz),4.37-4.44 (2H, m).

Step B

Benzoyl chloride (39.8 mL) was added at room temperature to an NMPsolution (200 mL) of (2S,3S)-butane-1,2,3,4-tetraol (19.0 g) and themixture was stirred at 50° C. for two hours. The reaction mixture wascooled to room temperature, and thereafter, water (800 mL) was added,and the mixture was stirred at room temperature for two hours. Thesolids were recovered by filtration and dissolved in ethyl acetate anddried with sodium sulfate. The solvent was eliminated by distillationunder reduced pressure, and the obtained solids were washed with ethylacetate/hexane liquid mixture, and (2S,3S)-2,3-dihydroxybutane-1,4-diyldibenzoate (31.6 g) was obtained.

MS. found: 353.1.

Step C

Chlorotrimethylsilane (16.3 mL) was added with ice cooling to a mixtureof (2S,3S)-2,3-dihydroxybutane-1,4-diyl dibenzoate (20.0 g),N,N-dimethyl-4-aminopyridine (0.74 g), triethylamine (18.6 mL) and DMF(300 mL), and the mixture was stirred at the same temperature for twohours. The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The liquidextract was washed with water and saturated aqueous sodium chloridesolution and was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure, and(2S,3S)-2,3-bis((trimethylsilyl)oxy)butane-1,4-diyl dibenzoate (22.5 g)was obtained as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 0.15-0.19 (18H, m), 4.09-4.16 (2H, m),4.34-4.43 (2H, m), 4.47-4.57 (2H, m), 7.42-7.51 (4H, m), 7.51-7.60 (2H,m), 8.03-8.08 (4H, m).

Step D

TMSOTf (176 μL) was added with ice cooling to a mixture of ethyl6-(acetylsulfanyl)-3,3-dimethoxycyclohex-1-ene-1-carboxylate (5.61 g),(2S,3S)-2,3-bis((trimethylsilyl)oxy)butane-1,4-diyldibenzoate (12.0 g)and acetonitrile (100 mL), and the mixture was stirred at the sametemperature for one hour. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane). The obtained solids wererecrystallized from ethyl acetate/hexane and ethyl(2S,3S)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (10.1 g) was obtained.

MS. found: 577.1.

Step E

Potassium carbonate (202 mg) was added with ice cooling to a mixture ofethyl(2S,3S)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (270 mg), 1-bromo-4-chloroindane (113 mg)and methanol (8 mL), and the mixture was stirred at room temperature forthree hours. The reaction mixture was diluted with 1N hydrochloric acidand extraction was performed with an ethyl acetate/THF liquid mixture.The liquid extract was washed with saturated aqueous sodium chloridesolution and was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (177 mg) was obtained as a colorless oilysubstance.

MS. found: 477.3.

Step F

mCPBA (205 mg, 72%) was added with ice cooling to an acetonitrilesolution (4 mL) of ethyl(2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (177 mg) and the mixture was stirred at50° C. for three hours. The reaction mixture was diluted with water, andextracted with ethyl acetate. The liquid extract was washed withsaturated aqueous sodium chloride solution and was dried with magnesiumsulfate, and the solvent was eliminated by distillation under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) and then separated and recovered twice using HPLC(C18, mobile phase: water/acetonitrile (0.1% TFA containing system)) andethyl(2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (26.0 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.32-1.38 (3H, m), 1.91-2.07 (2H, m),2.39-2.61 (3H, m), 2.82-3.04 (2H, m), 3.22-3.32 (1H, m), 3.67-3.75 (2H,m), 3.81-3.90 (2H, m), 4.01-4.35 (6H, m), 4.54-4.92 (2H, m), 6.91-7.03(1H, m), 7.17-7.23 (1H, m), 7.29-7.33 (1H, m), 7.47-7.58 (1H, m).

Example 4 Ethyl6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-3-hydroxycyclohex-1-ene-1-carboxylate(racemate, low polarity) Example 5 Ethyl6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-3-hydroxycyclohex-1-ene-1-carboxylate(racemate, high polarity)

Step A

Sodium borohydride (3.41 g) was added with ice cooling to an ethanolsolution (200 mL) of 7-chloroindan-1-one (10.0 g) and the mixture wasstirred overnight at room temperature. About half of the solvent waseliminated by distillation under reduced pressure, and water was addedto the residue and extraction was performed with ethyl acetate. Theliquid extract was washed with saturated aqueous sodium chloridesolution and was dried with sodium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) and7-chloroindan-1-ol (8.82 g) was obtained as a straw-colored oilysubstance.

¹H NMR (400 MHz, CDCl₃) δ 2.06-2.16 (1H, m), 2.30 (1H, d, J=2.9 Hz),2.37-2.47 (1H, m), 2.82-2.91 (1H, m), 3.15-3.24 (1H, m), 5.40-5.45 (1H,m), 7.14-7.23 (3H, m).

Step B

Diethyl ether solution (10 mL) of phosphorous tribromide (5.43 mL) wasadded at 0° C. to a diethyl ether solution (200 mL) of7-chloroindan-1-ol (8.82 g) and the mixture was stirred at the sametemperature for two hours. The reaction mixture was diluted with waterand extracted with ethyl acetate. The liquid extract was washed withsaturated aqueous sodium chloride solution and was dried with magnesiumsulfate, and the solvent was eliminated by distillation under reducedpressure, and 1-bromo-7-chloroindane (11.8 g) was obtained as astraw-colored oily substance.

¹H NMR (300 MHz, CDCl₃) δ 2.51-2.58 (2H, m), 2.87-2.96 (1H, m),3.22-3.37 (1H, m), 5.56-5.62 (1H, m), 7.14-7.22 (3H, m).

Step C

Sodium borohydride (0.24 g) was added with ice cooling to a mixture ofethyl 6-(acetylsulfanyl)-3-oxocyclohex-1-ene-1-carboxylate (1.56 g),cerium chloride (III) (2.88 g), ethanol (35 mL), and the mixture wasstirred at the same temperature for three hours. The reaction mixturewas diluted with water, and extracted with ethyl acetate. The liquidextract was washed with saturated aqueous sodium chloride solution andwas dried with magnesium sulfate, and the solvent was eliminated bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) and ethyl3-hydroxy-6-sulfanylcyclohex-1-ene-1-carboxylate (single relativeconfiguration) (361 mg) was obtained as a colorless oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.0 Hz), 1.75 (1H, brs),1.84-1.93 (1H, m), 1.99-2.12 (3H, m), 2.19 (1H, d, J=7.2 Hz), 3.95-4.02(1H, m), 4.25 (2H, q, J=7.2 Hz), 4.34-4.41 (1H, m), 6.76-6.79 (1H, m).

Step D

Potassium carbonate (247 mg) was added with ice cooling to a mixture ofethyl 3-hydroxy-6-sulfanylcyclohex-1-ene-1-carboxylate (single relativeconfiguration) (361 mg), 1-bromo-7-chloroindane (413 mg) and methanol (6mL), and the mixture was stirred at the same temperature for two hours.The reaction mixture was diluted with 1N hydrochloric acid and extractedwith ethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-3-hydroxycyclohex-1-ene-1-carboxylate(a mixture of 4 stereoisomers) (245 mg) obtained as a colorless oilysubstance.

MS. found: 375.1.

Step E

mCPBA (646 mg, 72%) was added with ice cooling to an acetonitrilesolution (8 mL) of ethyl6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-3-hydroxycyclohex-1-ene-1-carboxylate(a mixture of 4 stereoisomers) (432 mg) and the mixture was stirred atroom temperature for five hours. The reaction mixture was diluted withsaturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with magnesium sulfate, and the solventwas eliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) anda fraction of a low polarity compound and a fraction of a high polaritycompound were recovered, and these were respectively concentrated, andethyl6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-3-hydroxycyclohex-1-ene-1-carboxylate(racemate) was obtained.

Low polarity compound (yield 37 mg) ¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H,t, J=7.2 Hz), 1.83-2.14 (4H, m), 2.32-2.51 (2H, m), 2.82-2.99 (2H, m),3.36-3.48 (1H, m), 4.27-4.35 (3H, m), 4.85-4.90 (1H, m), 5.06 (1H, d,J=7.9 Hz), 7.19-7.25 (4H, m).

High polarity compound (yield 57 mg) ¹H NMR (300 MHz, CDCl₃) δ 1.24 (3H,t, J=7.0 Hz), 1.87-2.16 (4H, m), 2.47-2.64 (2H, m), 2.70-2.80 (1H, m),2.86-2.95 (1H, m), 3.45-3.59 (1H, m), 4.16-4.26 (2H, m), 4.30-4.39 (1H,m), 4.52-4.57 (1H, m), 5.10 (1H, d, J=7.9 Hz), 7.19-7.25 (4H, m).

Example 6 Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Step A

Potassium carbonate (5.70 g) was added with ice cooling to a mixture ofethyl(2R,3R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (7.63 g), 1-bromo-7-chloroindane (3.19 g)and methanol (100 mL), and the mixture was stirred at room temperaturefor one hour. The reaction mixture was diluted with 1N hydrochloricacid, and extraction was performed with an ethyl acetate/THF liquidmixture. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with magnesium sulfate, and the solventwas eliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (3.86 g) was obtained as a colorlesssolid.

MS. found: 477.1.

Step B

mCPBA (4.68 g, 72%) was added with ice cooling to a mixture of ethyl(2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (3.86 g), acetonitrile (60 mL) and DMF(30 mL) and the mixture was stirred at room temperature for four hours.The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The liquidextract was washed with water and saturated aqueous sodium chloridesolution and was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (3.23 g) was obtained as a colorless oilysubstance.

MS. found: 504.1.

Step C

Ethyl(2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (100 mg) was separated and recoveredusing HPLC (column=CHIRALPAK IC, 50 mmID×500 mmL, mobile phase:hexane/ethyl acetate=20/80), and the fractions from the first peak andthe second peak were recovered, combined, and concentrated (50 mg). 30mg of the residue was separated and recovered by HPLC (column=CHIRALPAKIC, 50 mmID×500 mmL, mobile phase: 2-propanol), and the fraction fromthe second peak was recovered and concentrated, and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(18 mg) was thereby obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.22 (3H, t, J=7.0 Hz), 1.90-1.99 (2H, m),2.14-2.32 (2H, m), 2.42-2.64 (3H, m), 2.71-2.80 (1H, m), 2.84-2.95 (1H,m), 3.43-3.57 (1H, m), 3.67-3.77 (2H, m), 3.80-3.93 (2H, m), 4.07-4.26(4H, m), 4.57 (1H, d, J=4.2 Hz), 5.10 (1H, d, J=7.9 Hz), 6.97-7.00 (1H,m), 7.17-7.25 (3H, m).

The Compound of Example 6 can be synthesized using a method of synthesisas per following Step D to Step I.

Step D

Borane dimethyl sulfide complex (12.1 mL) was added with ice coolingunder a nitrogen atmosphere to a THF solution (200 mL) of 1M(3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(toluene solution, 48.0 mL) and the mixture was stirred at the sametemperature for 30 minutes. A THF solution (130 mL) of7-chloroindan-1-one (20.0 g) was added with ice cooling to the reactionmixture, and the mixture was stirred at the same temperature for onehour. Methanol (48.6 mL) was added to the reaction mixture, andconcentration was performed under reduced pressure. The residue wasdiluted with 1N hydrochloric acid and extraction was performed with aliquid mixture of ethyl acetate/THF. The aqueous phase was extractedwith ethyl acetate, and the extracts were combined and washed withsaturated aqueous sodium chloride solution and dried with sodiumsulfate, and the solvent was eliminated by distillation under reducedpressure. The residue was filtered through silica gel, and elutionperformed with ethyl acetate. The solvent was eliminated by distillationunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane). The obtained solids wererecrystallized from toluene/hexane, and washed with a mixed solvent ofcool toluene/hexane, and (1S)-7-chloroindan-1-ol (11.1 g) was obtained.Optical purity 99.8% ee (analytic conditions; CHIRALCEL OD, 4.6 mmID×250mmL, mobile phase: hexane/2-propanol=90/10, flow rate: 1.0 mL/min,column temperature: 30° C.)

¹H NMR (300 MHz, CDCl₃) δ 2.11 (1H, dddd, J=13.9, 8.6, 4.2, 3.2 Hz),2.27 (1H, d, J=3.8 Hz), 2.42 (1H, ddt, J=14.1, 8.7, 6.9 Hz), 2.87 (1H,ddd, J=16.3, 9.0, 4.2 Hz), 3.20 (1H, dt, J=16.1, 7.8 Hz), 5.43 (1H, dt,J=6.8, 3.4 Hz), 7.11-7.24 (3H, m).

The compound of Step D can also be synthesized according to thesynthesis method shown in Step D′.

(Step D′)

To a suspension of 7-chloroindan-1-one (25.0 g), potassium formate (25.2g), 2-propanol (1.242 mL) and water (186 mL) was addedchloro(((1S,2S)-(+)-2-amino-1,2-diphenylethyl)(4-toluenesulfonyl)amide)(p-cymene)ruthenium(II)(0.955 g) at room temperature, and the mixture was stirred overnight at50° C. under argon atmosphere. The obtained mixture was extracted withethyl acetate, and the extract was washed with saturated brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane). To the obtained oil was addedhexane (20 mL), and the mixture was solidified in a freezer. Hexane (200mL) was added thereto, and the mixture was stirred at room temperaturefor 1 hr. The resulting solid was collected by filtration, and washedwith hexane. The obtained solid was recrystallized from toluene, and(1S)-7-chloroindan-1-ol (5.19 g) was obtained as a white solid. Opticalpurity 99.5% ee (analysis condition; column: CHIRALCEL ODH, 4.6 mmID×250mmL, mobile phase: hexane/2-propanol=90/10, flow rate: 1.0 mL/min,column temperature: 30° C.). The mother liquor and washing werecombined, and concentrated to dryness, and the obtained solid wasrecrystallized from hexane, and additional (1S)-7-chloroindan-1-ol (13.2g) was obtained as a white solid. Optical purity 99.5% ee (analysiscondition; column: CHIRALCEL ODH, 4.6 mmID×250 mmL, mobile phase:hexane/2-propanol=90/10, flow rate: 1.0 mL/min, column temperature: 30°C.).

Step E

Phosphorous tribromide (2.80 mL) was added at 10° C. to a diethyl ethersolution (150 mL) of (1S)-7-chloroindan-1-ol (5.0 g) and the mixture wasstirred at the same temperature for two hours. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure, and(1R)-1-bromo-7-chloroindane (6.13 g) was obtained as a colorless oilysubstance.

¹H NMR (300 MHz, CDCl₃) δ 2.52-2.59 (2H, m), 2.87-2.97 (1H, m),3.22-3.37 (1H, m), 5.57-5.62 (1H, m), 7.15-7.23 (3H, m).

Step F

Potassium carbonate (11.9 g) was added with ice cooling to a methanolsolution (281 mL) of ethyl(2R,3R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomer) (15.6 g) and the mixture was stirred atthe same temperature for one hour. 1N hydrochloric acid (215 mL) wasadded to the reaction mixture and extraction was performed with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with sodium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2R,3R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (6.39 g) was obtained as a straw-coloredoily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.2 Hz), 1.81-2.03 (3H, m),2.07-2.36 (4H, m), 3.66-4.32 (9H, m), 6.47-6.63 (1H, m).

Step G

Ethyl(2R,3R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (7.50 g) was crystallized from toluene (5mL) and pulverized in a mixed solvent of toluene/IPE=10/1. The solidswere recovered by filtration, and ethyl(2R,3R,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(1.82 g) was obtained as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.2 Hz), 1.83-2.32 (7H, m),3.65-4.34 (9H, m), 6.58 (1H, s).

Step H

A THF solution (19 mL) of DBU (2.28 g) was added with ice cooling to amixture of ethyl(2R,3R,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(3.50 g), (1R)-1-bromo-7-chloroindane (3.99 g) and THF (38 mL), and themixture was stirred at the same temperature for one hour. The reactionmixture was diluted with water and extracted with ethyl acetate. Theliquid extract was washed with saturated aqueous sodium chloridesolution and was dried with sodium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane). Theobtained oil was kept in a freezer for 3 days, and crystallized fromacetonitrile using the solid partially formed, and the solids recoveredby filtration were recrystallized from acetonitrile/hexane, and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(2.60 g) was obtained as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.30 (3H, t, J=7.2 Hz), 1.82-1.96 (3H, m),2.02-2.40 (4H, m), 2.45-2.58 (1H, m), 2.89 (1H, dd, J=16.3, 8.2 Hz),3.23-3.36 (1H, m), 3.64-3.76 (2H, m), 3.79-3.95 (3H, m), 4.05-4.33 (4H,m), 4.68 (1H, d, J=6.8 Hz), 6.54 (1H, s), 7.08-7.17 (3H, m).

Step I

mCPBA (3.10 g, 70%) was added with ice cooling to a mixture of ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(2.60 g), acetonitrile (20 mL) and DMF (20 mL), and the mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The liquid extract waswashed with water, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution and was dried with sodiumsulfate, and the solvent was eliminated by distillation under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) and the residue was crystallized from ethylacetate/hexane. The solids recovered by filtration were recrystallizedfrom ethyl acetate/heptane, and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(1.69 g) was obtained as a white solid.

Example 7 Ethyl(2S,3S,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Step A

Potassium carbonate (3.74 g) was added with ice cooling to a mixture ofethyl (2S,3S)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (5.0 g), 1-bromo-7-chloroindane (2.09 g)and methanol (80 mL), and the mixture was stirred at room temperaturefor one hour. The reaction mixture was diluted with 1N hydrochloricacid, and extraction was performed with ethyl acetate/THF liquidmixture. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with magnesium sulfate, and the solventwas eliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (2.16 g) was obtained as a colorlesssolid.

MS. found: 477.1.

Step B

mCPBA (2.84 g, 72%) was added at room temperature to a mixture of ethyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(2.16 g), acetonitrile (30 mL) and DMF (30 mL), and the mixture wasstirred at room temperature for five hours. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (1.60 g) was obtained as a colorlesssolid.

MS. found: 509.1.

Step C

Ethyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (800 mg) was separated and recovered byHPLC (column=CHIRALPAK IC, 50 mmID×500 mmL, mobile phase: hexane/ethylacetate=40/60), and the fractionated fraction from the fourth peak wasrecovered and concentrated, and ethyl(2S,3S,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(196 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7.0 Hz), 1.86-2.05 (3H, m),2.15-2.28 (1H, m), 2.41-2.62 (3H, m), 2.71-2.81 (1H, m), 2.85-2.95 (1H,m), 3.44-3.57 (1H, m), 3.67-3.77 (2H, m), 3.81-3.91 (2H, m), 3.99-4.06(1H, m), 4.10-4.26 (3H, m), 4.57 (1H, d, J=4.9 Hz), 5.08 (1H, d, J=8.3Hz), 6.90-6.93 (1H, m), 7.17-7.25 (3H, m).

Example 8 (1-methylcyclopropyl)methyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers)

Step A

0.75M barium hydroxide octahydrate aqueous solution (23.7 mL) was addedto an acetonitrile solution (60 mL) of ethyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (2.7 g) and the mixture was stirred at60° C. for two hours. The reaction mixture was diluted with 1Nhydrochloric acid and extracted with ethyl acetate. The organic phasewas extracted with 1N aqueous sodium hydroxide solution and was washedwith ethyl acetate. The aqueous phase was made acidic (pH=3 to 4) with2N hydrochloric acid and extracted with ethyl acetate. The liquidextract was washed with saturated aqueous sodium chloride solution andwas dried with magnesium sulfate, and the solvent was eliminated bydistillation under reduced pressure, and(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylicacid (a mixture of 4 diastereomers) (2.45 g) was obtained as a paleyellow solid.

MS. found: 449.1.

Step B

Diethyl diazene-1,2-dicarboxylate (40% toluene solution, 632 mg) wasadded with ice cooling to a mixture of(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylicacid (a mixture of 4 diastereomers) (310 mg),(1-methylcyclopropyl)methanol (96 μL), triphenylphosphine (381 mg) andTHF (6 mL), and the mixture was stirred overnight while warming to roomtemperature. The reaction mixture was diluted with water, and extractedwith ethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and (1-methylcyclopropyl)methyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (206 mg) was obtained as a colorlesssolid.

MS. found: 518.2.

Step C

mCPBA (219 mg, 72%) was added with ice cooling to a mixture of(1-methylcyclopropyl)methyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (206 mg), acetonitrile (1.5 mL) and DMF(3 mL), and the mixture was stirred at room temperature for four hours.The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The liquidextract was washed with water and saturated aqueous sodium chloridesolution and was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) and(1-methylcyclopropyl)methyl(2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 4 diastereomers) (75 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 0.33-0.57 (4H, m), 1.08-1.22 (3H, m),1.77-2.08 (4H, m), 2.14-2.30 (1.5H, m), 2.35-2.53 (2H, m), 2.57-2.64(0.5H, m), 2.71-2.99 (2H, m), 3.38-3.55 (1H, m), 3.66-3.76 (2H, m),3.80-3.91 (2H, m), 4.00-4.11 (2H, m), 4.15-4.25 (1H, m), 4.53-4.57(0.5H, m), 4.91-4.99 (0.5H, m), 5.03-5.13 (1H, m), 6.91-7.04 (1H, m),7.16-7.25 (3H, m).

Example 14 Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Step A

Borane dimethyl sulfide complex (15.0 mL) was added with ice coolingunder a nitrogen atmosphere to a THF solution (100 mL) of(3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(3.0 g) and the mixture was stirred at the same temperature for onehour. A THF solution (20 mL) of 7-chloro-5-fluoroindan-1-one (5.0 g) wasadded at −78° C. to the reaction mixture, and the mixture was stirredovernight while warming to room temperature. The reaction mixture wasdiluted with ice cooling with methanol, and the reaction mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) and(1S)-7-chloro-5-fluoroindan-1-ol (4.87 g) was obtained as astraw-colored solid.

¹H NMR (300 MHz, CDCl₃) δ 2.08-2.21 (2H, m), 2.37-2.50 (1H, m),2.80-2.91 (1H, m), 3.13-3.26 (1H, m), 5.35-5.41 (1H, m), 6.84-6.97 (2H,m).

Step B

Phosphorous tribromide (505 μL) was added at −78° C. to a diethyl ethersolution (20 mL) of (1S)-7-chloro-5-fluoroindan-1-ol (1.0 g) and themixture was stirred for two hours while warming to 0° C. The reactionmixture was diluted with saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The liquid extract was washed withsaturated aqueous sodium chloride solution and was dried with magnesiumsulfate, and the solvent was eliminated by distillation under reducedpressure, and (1R)-1-bromo-7-chloro-5-fluoroindan (1.33 g) was obtainedas a straw-colored oily substance.

¹H NMR (300 MHz, CDCl₃) δ 2.54-2.62 (2H, m), 2.86-2.95 (1H, m),3.22-3.36 (1H, m), 5.51-5.57 (1H, m), 6.85-6.99 (2H, m).

Step C

DBU (0.16 mL) was added with ice cooling to a mixture of ethyl(2R,3R,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(286 mg), (1R)-1-bromo-7-chloro-5-fluoroindan (305 mg) and THF (6 mL),and the mixture was stirred at room temperature for one hour. Thereaction mixture was diluted with water and extracted with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with magnesium sulfate, and the solventwas eliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(450 mg) was obtained as a colorless oily substance.

MS. found: 495.1.

Step D

mCPBA (506 mg, 72%) was added with ice cooling to a mixture of ethyl(2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(454 mg), acetonitrile (4 mL) and DMF (4 mL), and the mixture wasstirred at room temperature for six hours. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate. The liquid extract was washed with water andsaturated aqueous sodium chloride solution and was dried with magnesiumsulfate, and the solvent was eliminated by distillation under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) and then crystallized from ethyl acetate/hexane.The solids recovered by filtration were recrystallized twice from ethylacetate/hexane, and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(64 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (3H, t, J=7.2 Hz), 1.88-2.00 (2H, m),2.13-2.27 (2H, m), 2.37-2.66 (3H, m), 2.68-2.77 (1H, m), 2.83-2.94 (1H,m), 3.43-3.57 (1H, m), 3.67-3.76 (2H, m), 3.80-3.93 (2H, m), 4.07-4.30(4H, m), 4.51-4.55 (1H, m), 5.09 (1H, d, J=7.9 Hz), 6.89-7.01 (3H, m).

Example 15 Ethyl(2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Step A

Ethyl(2S,3S)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (3.0 g) was separated and recovered usingHPLC (column=CHIRALPAK IA, 50 mmID×500 mmL, mobile phase:hexane/ethanol=50/50) and the first peak fraction was concentrated, andethyl(2S,3S,8R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (1.36 g) was obtained as a white solid.

MS. found: 577.2.

Step B

Potassium carbonate (632 mg) was added with ice cooling to a mixture ofethyl(2S,3S,8R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(846 mg), methanol (8 mL) and THF (8 mL), and the mixture was stirred atthe same temperature for one hour. Chlorotrimethylsilane (1.35 mL) wasadded to the reaction mixture, and the mixture was diluted withsaturated aqueous sodium chloride solution and extracted with ethylacetate. The liquid extract was dried with sodium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl(2S,3S,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(368 mg) was obtained as a colorless oily substance.

MS=(M−H)−303.0.

Step C

DBU (94 μL) was added with ice cooling to a mixture of ethyl(2S,3S,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(173 mg), (1R)-1-bromo-7-chloro-5-fluoroindan (184 mg) and THF (2 mL),and the mixture was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with water, and extracted with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with sodium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl(2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(145 mg) was obtained as a colorless oily substance.

MS. found: 495.1.

Step D

mCPBA (227 mg, 70%) was added with ice cooling to a mixture of ethyl(2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(145 mg), acetonitrile (1 mL) and DMF (0.5 mL), and the mixture wasstirred at room temperature for one hour. The reaction mixture wasdiluted with saturated aqueous sodium thiosulfate solution and extractedwith ethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with sodium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and then was separated and recovered using HPLC(column=CHIRALPAK IA, 50 mmID×500 mmL, mobile phase:hexane/ethanol=20/80) and the obtained fraction was concentrated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl(2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(31 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (3H, t, J=7.2 Hz), 1.87-1.96 (1H, m),2.12-2.29 (1H, m), 2.33-2.47 (1H, m), 2.49-2.66 (2H, m), 2.68-2.80 (1H,m), 2.89 (1H, dd, J=16.2, 8.7 Hz), 3.42-3.60 (1H, m), 3.67-3.78 (2H, m),3.81-3.91 (2H, m), 3.98-4.08 (1H, m), 4.14-4.34 (3H, m), 4.52 (1H, d,J=4.9 Hz), 5.08 (1H, d, J=7.9 Hz), 6.88-6.94 (2H, m), 6.98 (1H, dd,J=8.7, 1.9 Hz).

Example 16 Ethyl(2R,3R,8R)-8-((8-chloro-1,2,3,4-tetrahydronaphthalen-1-0)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(single diastereomer, the first peak) Example 17 Ethyl(2R,3R,8R)-8-((8-chloro-1,2,3,4-tetrahydronaphthalen-1-0)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(single diastereomer, the second peak)

Step A

A mixture of 3,4-dihydronaphthalen-1(2H)-one (5.90 g),O-methylhydroxylamine hydrochloride (5.06 g), pyridine (4 mL) andethanol (80 mL) was heated under reflux for two hours and 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was diluted with 1N hydrochloric acid, and extracted with ethylacetate. The liquid extract was washed with water and saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and N-methoxy-3,4-dihydronaphthalen-1(2H)-imine (6.96 g)was obtained as a colorless oily substance.

¹H NMR (300 MHz, DMSO-d₆) δ 1.68-1.81 (2H, m), 2.63-2.73 (4H, m), 3.90(3H, s), 7.14-7.23 (2H, m), 7.24-7.32 (1H, m), 7.77-7.88 (1H, m).

Step B

Palladium (II) acetate (106 mg) was added at room temperature to amixture of N-methoxy-3,4-dihydronaphthalen-1(2H)-imine (1.65 g),N-chlorosuccinimide (1.32 g) and acetic acid (60 mL), and the mixturewas stirred at 90° C. for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted with 2Naqueous sodium hydroxide solution and extraction was performed withethyl acetate. The liquid extract was washed with water and saturatedaqueous sodium chloride solution and was dried with magnesium sulfate,and the solvent was eliminated by distillation under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) and 8-chloro-N-methoxy-3,4-dihydronaphthalen-1(2H)-imine(1.78 g) was obtained as a colorless oily substance.

MS: [M+H]⁺ 210.1.

Step C

A mixture of 8-chloro-N-methoxy-3,4-dihydro-naphthalen-1(2H)-imine (1.78g), 6N hydrochloric acid (30 mL) and DME (20 mL) was heated under refluxfor three hours. The reaction mixture was extracted with ethyl acetate.The liquid extract was washed with water and saturated aqueous sodiumchloride solution and was dried with magnesium sulfate, and the solventwas eliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) and8-chloro-3,4-dihydronaphthalen-1(2H)-one (1.34 g) was obtained as acolorless oily substance.

¹H NMR (300 MHz, DMSO-d₆) δ 1.94-2.07 (2H, m), 2.62 (2H, t, J=6.6 Hz),2.96 (2H, t, J=6.2 Hz), 7.29-7.41 (2H, m), 7.43-7.51 (1H, m).

Step D

Sodium borohydride (0.63 g) was added with ice cooling to an ethanolsolution (50 mL) of 8-chloro-3,4-dihydro-naphthalen-1(2H)-one (2.0 g)and the mixture was stirred overnight at room temperature. About half ofthe solvent was eliminated by distillation under reduced pressure, andwater was added to the residue, and extraction was performed with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with sodium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) and8-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (2.03 g) was obtained as acolorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.73-1.84 (2H, m), 1.91-2.03 (1H, m),2.15-2.24 (1H, m), 2.36 (1H, dd, J=3.8, 1.1 Hz), 2.64-2.77 (1H, m),2.81-2.91 (1H, m), 5.06-5.11 (1H, m), 7.02-7.07 (1H, m), 7.14 (1H, t,J=7.7 Hz), 7.21-7.25 (1H, m).

Step E

8-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (2.03 g) was added at 0° C.to a diethyl ether solution (50 mL) of phosphorous tribromide (1.05 mL)and the mixture was stirred at the same temperature for two hours. Thereaction mixture was diluted with water, and extracted with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution and was dried with magnesium sulfate, and the solventwas eliminated by distillation under reduced pressure, and1-bromo-8-chloro-1,2,3,4-tetrahydronaphthalene (2.54 g) was obtained asa straw-colored oily substance.

MS=(M−H)−244.8.

Step F

DBU (0.125 mL) was added with ice cooling to a mixture of ethyl(2R,3R,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(230 mg), 1-bromo-8-chloro-1,2,3,4-tetrahydronaphthalene (186 mg) andTHF (6 mL), and the mixture was stirred at the same temperature for onehour. The reaction mixture was diluted with water and extracted withethyl acetate. The liquid extract was washed with saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl(2R,3R,8R)-8-((8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (269 mg) was obtained as a colorlesssolid.

MS. found: 491.2.

Step G

mCPBA (302 mg, 72%) was added with ice cooling to a mixture of ethyl(2R,3R,8R)-8-((8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(a mixture of 2 diastereomers) (269 mg), acetonitrile (3 mL) and DMF (3mL), and the mixture was stirred overnight at room temperature. Thereaction mixture was diluted with saturated aqueous sodium bicarbonatesolution and extracted with ethyl acetate. The liquid extract was washedwith saturated aqueous sodium chloride solution and was dried withmagnesium sulfate, and the solvent was eliminated by distillation underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and then separated and recoveredusing HPLC (column=CHIRALPAK AD, 50 mmID×500 mmL, mobile phase:hexane/2-propanol=75/25). The fractions from the first peak and thesecond peak were each concentrated, and ethyl(2R,3R,8R)-8-((8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(as single diastereomers) was obtained.

The first peak (yield 98.5 mg)¹H NMR (300 MHz, CDCl₃) δ 1.18 (3H, t,J=7.0 Hz), 1.57-1.67 (1H, m), 1.87-1.99 (2H, m), 2.11-2.34 (4H, m),2.49-2.74 (4H, m), 3.05-3.16 (1H, m), 3.66-3.75 (2H, m), 3.80-3.92 (2H,m), 4.06-4.21 (4H, m), 4.56 (1H, d, J=4.2 Hz), 5.20 (1H, dd, J=7.6, 2.6Hz), 6.96-6.98 (1H, m), 7.07-7.12 (1H, m), 7.20 (1H, t, J=7.7 Hz),7.26-7.29 (1H, m).

The second peak (yield 45.5 mg) ¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t,J=7.2 Hz), 1.65-1.74 (1H, m), 1.84-2.10 (5H, m), 2.23-2.37 (2H, m),2.63-2.75 (2H, m), 3.01-3.14 (1H, m), 3.66-3.75 (2H, m), 3.79-3.93 (2H,m), 4.00-4.23 (3H, m), 4.27-4.36 (2H, m), 4.87 (1H, d, J=4.9 Hz), 5.27(1H, dd, J=6.4, 1.9 Hz), 6.93-6.97 (1H, m), 7.11 (1H, d, J=7.6 Hz),7.18-7.24 (1H, m), 7.27-7.31 (1H, m).

Example 18 Ethyl(6R)-6-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)cyclohex-1-ene-1-carboxylate

Step A

DBU (0.37 mL) was added with ice cooling to a mixture of ethyl6-sulfanylcyclohex-1-ene-1-carboxylate (0.42 g),(1R)-1-bromo-7-chloro-5-fluoroindan (0.63 g) and THF (5 mL), and themixture was stirred at the same temperature for one hour. The reactionmixture was diluted with water and extracted with ethyl acetate. Theliquid extract was washed with saturated aqueous sodium chloridesolution and was dried with sodium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andthen was separated and recovered using HPLC (C18, mobile phase:water/acetonitrile (system containing 0.1% TFA) and the first peakfraction was concentrated, and ethyl(6R)-6-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)cyclohex-1-ene-1-carboxylate(270 mg) was obtained as a colorless oily substance.

MS. found: 359.0.

Step B

mCPBA (494 mg, 70%) was added with ice cooling to a mixture of ethyl(6R)-6-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)cyclohex-1-ene-1-carboxylate(270 mg) and acetonitrile (3 mL), and the mixture was stirred at roomtemperature for one hour. The reaction mixture was diluted withsaturated aqueous sodium thiosulfate solution and extracted with ethylacetate. The liquid extract was washed with saturated aqueous sodiumbicarbonate solution (twice) and saturated aqueous sodium chloridesolution and then was dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andthen recrystallized from ethyl acetate/IPE. The obtained solids wereseparated and recovered using SFC (column=CHIRALPAK AD-H, 20 mmID×250mmL, mobile phase: carbon dioxide/2-propanol=90/10) and the obtainedfraction was concentrated under reduced pressure, and ethyl(6R)-6-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)cyclohex-1-ene-1-carboxylate(176 mg) was obtained as a pale-brown solid.

¹H NMR (300 MHz, CDCl₃) δ 1.25 (3H, t, J=7.2 Hz), 1.64-1.84 (2H, m),1.96-2.34 (2H, m), 2.39-2.67 (3H, m), 2.76 (1H, dd, J=14.2, 7.4 Hz),2.89 (1H, dd, J=16.1, 8.9 Hz), 3.43-3.61 (1H, m), 4.09-4.30 (2H, m),4.59 (1H, d, J=5.7 Hz), 5.11 (1H, d, J=7.9 Hz), 7.14-7.25 (3H, m), 7.39(1H, t, J=4.0 Hz).

Example 19 Ethyl(2S,3S,8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Step A

Under a nitrogen atmosphere, borane dimethyl sulfide complex (2.91 mL)was added at −78° C. to a mixture of (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (0.61 g),8-chloro-3,4-dihydronaphthalen-1(2H)-one (1.0 g), and THF (30 mL), andit was stirred overnight while warming to room temperature. Methanol wasadded with ice cooling to the reaction mixture, and the mixtureconcentrated down and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane). The obtained solids wererecrystallized from toluene/hexane, and(1S)-8-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (0.69 g) was obtained asa colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.73-1.84 (2H, m), 1.91-2.04 (1H, m),2.15-2.24 (1H, m), 2.36 (1H, dd, J=3.8, 1.1 Hz), 2.64-2.77 (1H, m),2.81-2.91 (1H, m), 5.06-5.11 (1H, m), 7.03-7.07 (1H, m), 7.14 (1H, t,J=7.6 Hz), 7.21-7.25 (1H, m).

Step B

Phosphorous tribromide (118 μL) was added at −10° C. to a diethyl ethersolution (4 mL) of (1S)-8-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (230mg) and the mixture was stirred at the same temperature for 30 minutes.The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The liquidextract was washed with saturated aqueous sodium chloride solution andwas dried with sodium sulfate, and the solvent was eliminated bydistillation under reduced pressure, and(1R)-1-bromo-8-chloro-1,2,3,4-tetrahydronaphthalene (196 mg) wasobtained as a brown oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.88-2.02 (1H, m), 2.03-2.13 (1H, m),2.23-2.41 (1H, m), 2.41-2.53 (1H, m), 2.79-3.07 (2H, m), 5.68 (1H, brs),7.01 (1H, d, J=7.6 Hz), 7.10-7.18 (1H, m), 7.19-7.25 (1H, m).

Step C

DBU (0.15 mL) was added with ice cooling to a mixture of ethyl(2S,3S,8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(368 mg), (1R)-1-bromo-8-chloro-1,2,3,4-tetrahydronaphthalene (196 mg)and THF (3 mL), and the mixture was stirred at the same temperature forone hour. The reaction mixture was diluted with water and extracted withethyl acetate. The liquid extract was dried with sodium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and ethyl(2S,3S,8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(279 mg) was obtained as a colorless oily substance.

MS. found: 491.2.

Step D

mCPBA (367 mg, 70%) was added with ice cooling to a mixture of ethyl(2S,3S,8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(279 mg) and acetonitrile (5 mL), and the mixture was stirred at roomtemperature for three hours. The reaction mixture was diluted withsaturated aqueous sodium thiosulfate solution and extracted with ethylacetate. The liquid extract was washed with saturated aqueous sodiumchloride solution, dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andthen separated and recovered using SFC (column=CHIRALCEL OJ-H, 20mmID×250 mmL, mobile phase: carbon dioxide/methanol=86/14) and theobtained fraction was concentrated under reduced pressure. The residuewas crystallized from ethyl acetate/heptane, and ethyl(2S,3S,8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(47 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.18 (3H, t, J=7.2 Hz), 1.57-1.70 (1H, m),1.84-1.97 (2H, m), 2.00-2.09 (1H, m), 2.09-2.39 (3H, m), 2.46-2.55 (1H,m), 2.56-2.74 (3H, m), 3.02-3.18 (1H, m), 3.64-3.77 (2H, m), 3.80-3.93(2H, m), 3.97-4.24 (4H, m), 4.55 (1H, d, J=5.3 Hz), 5.19 (1H, dd, J=7.6,2.3 Hz), 6.86-6.92 (1H, m), 7.06-7.13 (1H, m), 7.16-7.24 (1H, m), 7.28(1H, s).

Example 20 Ethyl3-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate(a single diastereomer)

Step A

While keeping the internal temperature at 20° C. or less using icecooling, (3R,4S)-tetrahydrofuran-3,4-diol (45.0 g) was added dropwise toan aqueous solution (220 mL) of sodium periodate (97.0 g), and themixture was then stirred overnight at room temperature. Sodiumbicarbonate (7.26 g) and ethyl(diethoxyphosphoryl)acetate (60.6 mL) wereadded at room temperature to the reaction mixture, and the mixture wasstirred at the same temperature for three hours. Sodium bicarbonate(84.0 g) was added to the reaction mixture, and the mixture was stirredovernight at an internal temperature of 50° C. The reaction mixture wascooled to room temperature, and then the solids were eliminated byfiltration. The solids were washed with THF, and the washings werecombined with the filtrate. Sodium chloride was added to the mixture andextraction performed with ethyl acetate. The aqueous phase was extractedtwice further with an ethyl acetate/THF liquid mixture, and the extractswere combined and dried with magnesium sulfate, and the solvent waseliminated by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) andethyl 3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (25.8 g) was obtainedas a straw-colored oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J=7.2 Hz), 2.79 (1H, d, J=4.9Hz), 3.72 (1H, dd, J=11.9, 3.2 Hz), 3.95 (1H, dd, J=11.7, 3.0 Hz),4.18-4.43 (5H, m), 7.04-7.08 (1H, m).

Step B

Triethylamine (31.2 mL) was added with ice cooling to a THF (300 mL)solution of ethyl 3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (25.8 g)and the mixture was stirred at the same temperature for ten minutes.Methanesulfonyl chloride (14.5 mL) was added to the reaction mixture andthe mixture was stirred at the same temperature for 30 minutes. Thereaction mixture was diluted with ice cooled 1N hydrochloric acid andextracted with ethyl acetate. The liquid extract was washed withsaturated aqueous sodium chloride solution and was dried with sodiumsulfate, and the solvent was eliminated by distillation under reducedpressure. To a mixture of the residue and toluene (400 mL), weresuccessively added thioacetic acid (12.6 mL) and triethylamine (26.7 mL)under ice cooling and the mixture was stirred at the same temperaturefor 30 minutes. The reaction mixture was diluted with 1N hydrochloricacid and extracted with ethyl acetate. The liquid extract was washedwith saturated aqueous sodium chloride solution and was dried withmagnesium sulfate, and the solvent was eliminated by distillation underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and ethyl3-(acetylsulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate (24.7 g) wasobtained as a straw-colored oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.28 (3H, t, J=7.0 Hz), 2.34 (3H, s), 3.85(1H, dd, J=11.9, 2.5 Hz), 4.00 (1H, dd, J=12.1, 1.1 Hz), 4.17-4.31 (3H,m), 4.37-4.46 (1H, m), 4.52 (1H, brs), 7.05-7.09 (1H, m).

Step C

4N hydrochloric acid (ethyl acetate solution, 70 mL) was added at roomtemperature to an ethanol solution (70 mL) of ethyl3-(acetylsulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate (24.7 g) and themixture was stirred at 45° C. for 16 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) and ethyl3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (19.5 g) was obtained as astraw-colored oily substance.

¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J=7.2 Hz), 2.23 (1H, d, J=9.1Hz), 3.67-3.75 (1H, m), 3.85-3.93 (1H, m), 4.01 (1H, dd, J=11.7, 1.9Hz), 4.22-4.32 (3H, m), 4.37-4.47 (1H, m), 6.82-6.86 (1H, m).

Step D

DBU (0.34 mL) was added with ice cooling to a mixture of ethyl3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (0.43 g),(1R)-1-bromo-7-chloroindane (0.63 g) and THF (5 mL), and the mixture wasstirred at the same temperature for one hour. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The liquid extractwas washed with saturated aqueous sodium chloride solution and was driedwith sodium sulfate, and the solvent was eliminated by distillationunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and ethyl3-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate(a mixture of 2 diastereomers) (0.32 g) was obtained as a colorless oilysubstance.

¹H NMR (300 MHz, CDCl₃) δ 1.23-1.40 (3H, m), 2.23-2.60 (2H, m),2.77-2.96 (1H, m), 3.20-3.42 (1H, m), 3.70 (0.6H, brs), 3.75-3.92 (1.4H,m), 4.05 (0.6H, dd, J=11.7, 1.5 Hz), 4.16-4.33 (3.4H, m), 4.34-4.47 (1H,m), 4.53 (0.4H, d, J=6.4 Hz), 4.79 (0.6H, d, J=6.8 Hz), 6.85-6.92 (0.6H,m), 6.94-6.99 (0.4H, m), 7.06-7.21 (3H, m).

Step E

mCPBA (0.58 g, 70%) was added with ice cooling to a mixture of ethyl3-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate(a mixture of 2 diastereomers) (0.32 g) and acetonitrile (3 mL), and themixture was stirred at room temperature for one hour. The reactionmixture was diluted with saturated aqueous sodium thiosulfate solutionand extracted with ethyl acetate. The liquid extract was washed withsaturated aqueous sodium bicarbonate solution (twice) and saturatedaqueous sodium chloride solution and was dried with sodium sulfate, andthe solvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and the high polarity fraction was concentrated underreduced pressure. Of the obtained residue, 100 mg was separated andrecovered using SFC (column=CHIRALPAK AD-H, 20 mmID×250 mmL, mobilephase: carbon dioxide/methanol=77/23) and the first peak fraction wasconcentrated down under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) and ethyl3-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate(a single diastereomer) (36 mg) was obtained.

¹H NMR (300 MHz, CDCl₃) δ 1.31 (3H, t, J=7.2 Hz), 2.35-2.52 (1H, m),2.67 (1H, dd, J=14.2, 7.4 Hz), 2.87 (1H, dd, J=15.9, 8.7 Hz), 3.40-3.57(1H, m), 3.79 (1H, dd, J=12.7, 3.2 Hz), 4.23-4.41 (4H, m), 4.52-4.63(1H, m), 4.80-4.88 (1H, m), 5.24 (1H, d, J=7.6 Hz), 7.15-7.25 (4H, m).

Example 21 Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Step A

Sodium hydride (1.26 g, 60% oil) was added with ice cooling to a mixtureof ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(5.72 g), iodomethane (7.14 g) and DMF (50 mL), and the mixture wasstirred at the same temperature for one hour. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The liquid extractwas washed with water and saturated aqueous sodium chloride solution andwas washed with magnesium sulfate, and the solvent was eliminated bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(5.91 g) was obtained as a straw-colored oily substance.

MS. found: 532.2.

Step B

mCPBA (7.15 g, 65%) was added with ice cooling to a mixture of ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(5.91 g), DMF (50 mL) and acetonitrile (50 mL), and the mixture stirredovernight at room temperature. The reaction mixture was diluted withsaturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The liquid extract was washed with water and saturated aqueoussodium chloride solution and was dried with magnesium sulfate, and thesolvent was eliminated by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) and was crystallized from ethanol/hexane, and the solidswere recovered by filtration. The obtained solids were recrystallizedfrom ethyl acetate/heptane, and ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate(3.47 g) was obtained as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 1.19 (3H, t, J=7.2 Hz), 1.85-2.01 (1H, m),2.15-2.35 (1H, m), 2.39-2.62 (3H, m), 2.76 (1H, dd, J=14.4, 7.6 Hz),2.88 (1H, dd, J=16.2, 8.7 Hz), 3.40 (3H, s), 3.42 (3H, s), 3.44-3.66(5H, m), 3.98-4.07 (1H, m), 4.08-4.27 (3H, m), 4.49-4.58 (1H, m), 5.07(1H, d, J=8.3 Hz), 7.05 (1H, s), 7.13-7.25 (3H, m).

According to the methods shown in the Examples or methods analogousthereto, the compounds of Examples 9-13 in following tables wereproduced. The compounds of Examples are shown in the following Table. MSin the table means actual value.

TABLE 1 Example number IUPAC Name Structure MS 1 Ethyl6-((4-chloro-2,3-dihydro- 1H-inden-1-yl)sulfonyl)cyclohex-1-ene-1-carboxylate

368.9 2 Ethyl (2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dixoaspiro[4.5]dec-6-ene- 7-carboxylate

484.9 3 Ethyl (2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dixoaspiro[4.5]dec-6-ene- 7-carboxylate

485.1 4 Ethyl 6-((7-chloro-2,3-dihydro- 1H-inden-1-yl)sulfonyl)-3-hydroxycyclohex-1-ene-1-carboxylate

384.9 5 Ethyl 6-((7-chloro-2,3-dihydro- 1H-inden-1-yl)sulfonyl)-3-hydroxycyclohex-1-ene-1-carboxylate

384.9 6 Ethyl (2R, 3R, 8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate

485.0 7 Ethyl (2R, 3S, 8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate

485.0 8 (1-methylcyclopropyl)methyl(2S, 3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4,5]dec-6-ene-7-carboxylate

525.1 9 Ethyl(2S, 3S)-8-((7-chloro-4-fluoro-2,3-dihydro--1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

503.1 10 Ethyl (2S, 3S)-8-((7-chloro-6-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

503.0 11 Ethyl (2S, 3S)-8-((7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

546.9 12 Ethyl (2S, 3S)-8-((7-bromo-2,3-dihydro-1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4,5]dec-6-ene-7-carboxylate

531.0 13 Ethyl (2S, 3S)- 2,3-bis(hydroxymethyl)-8-((7-methyl-2,3-dihydro-1H-inden-1-yl)sulfonyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

14 Ethyl (2R, 3R, 8R)-8-(((1S)-7(chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

503.0 15 Ethyl (2R, 3R, 8R)-8-(((1S)-7-chloro-5-fluoro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

503.0 16 Ethyl (2R, 3R, 8R)-8-(8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate

499.1 17 Ethyl (2R, 3R, 8R)-8-(8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate

499.0 18 Ethyl (6R)-6-(((1S)-7-chloro-2,3-dihydro-1H-iden-1-yl)sulfonyl) cyclohex-1-ene-1-carboxylate

369.1 19 Ethyl (2S, 3S, 8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahydronaphthalen)-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate

499.1 20 Ethyl 3-(((1S)-7-chloro- 2,3-dihydro-1H-inden-1-yl)sulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate

371.0 21 Ethyl (2R, 3R, 8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1.4-dioxaspiro [4.5]dec-6-ene-7-carboxylate

515.1

The NMR of the compound of Example 13 is shown below.

¹H NMR (300 MHz, CDCl₃) δ 1.28-1.37 (3H, m), 2.07-2.30 (2H, m),2.33-2.43 (3H, m), 2.46-2.67 (4H, m), 2.76-2.92 (2H, m), 3.33-3.47 (1H,m), 3.61-3.86 (4H, m), 3.98-4.11 (1H, m), 4.15-4.37 (4H, m), 4.64-4.77(1H, m), 4.78-4.90 (0.25H, m), 5.03-5.09 (0.5H, m), 5.30 (0.25H, d,J=7.9 Hz), 7.00-7.25 (4H, m).

Test Example 1 Inhibitory Effect with Respect to NO Production

The inhibitory effect on TLR4 was determined using the inhibition ratedue to the test compound with respect to NO production as a result ofaddition of lipopolysaccharide (LPS) using murine macrophage cell lineRAW264.7. The cells were adjusted to 2×10⁶ cells/mL using RPM1-1640culture medium (phenol red free) supplemented with 10% inactivatedbovine fetal serum, and were plated on 384 well plate so as to contain6×10⁴ cells/30 μL per well. Thereafter the cells were cultured at 37° C.overnight under 5% CO₂195% air. The test compound dissolved in DMSO wasdiluted 200 times using RPM1-1640 culture medium and adjusted so as toform a compound concentration of 500 nM. The prepared test compound 10μL (final concentration 100 nM) was added to the cells, and LPS (Sigma)and mouse interferon γ (Wako Pure Chemicals) were added in amounts of 10μL so as to form final concentrations of 1.25 ng/mL and 0.2 ng/mLrespectively. The cells were further cultured overnight, and then thenitrite ion (stable NO metabolite) concentration in the culturesupernatant was measured as an index of NO production. The nitrite ionconcentration was assayed by adding 10 μL of 20 μg/mL 2,3-diaminonaphthalene (DAN) dissolved in 0.2N HCl to 20 μL culture supernatant,incubating at room temperature for ten minutes, and then adding 10 μL of0.5N NaOH, and measuring the fluorescent value at 460 nm (excitationwavelength 355 nm) using an EnVision plate reader (Perkin Elmer). The NOproduction inhibition rate (%) was calculated using the value withoutthe addition of stimulating agent as control of 100% inhibition, and thevalue without the addition of the compound as control of 0% inhibition.The results thereof are shown in Table 2.

TABLE 2 Compound NO production inhibitory effect at 100 nM No. (%inhibition) 1 96 2 99 3 110 4 110 5 100 6 103 7 105 8 99 9 110 10 100 11110 12 100 13 100 14 107 15 106 16 108 17 86 18 104 19 107 20 104 21 112

Test Example 2 Effect with Respect to Blood TNF-α ConcentrationElevation by LPS Stimulation

Various kinds of cytokines are produced in vivo accompanyinginflammatory response and abnormal immunity or the like. Therefore, theaction of test compound with respect to blood TNFα concentration risewas investigated using laboratory animals.

Female BALB/c mice (6 weeks old) were purchased, and, after preliminaryrearing for about 1 week, the mice were divided into groups of fouranimals. The test compound was dissolved in 10% captisol aqueoussolution and was intravenously administered to the test group at a doseof 3 mg/kg. Solvent was administered to control group in the same way.LPS (5 mg/kg) was administered intraperitoneally to the test group andthe control group one hour after the administration of the test compoundor solvent, and blood was sampled one hour later. The serum wasseparated from the obtained blood, and the TNFα concentration in theserum was measured using an assay kit made by R&D Systems Inc. Theinhibition rates of the test group with respect to the control group areshown in Table 3.

TABLE 3 Blood TNFα Compound inhibition rate No. (% inhibition) 6 93.1

Test Example 3 Action on Liver Injury by Galactosamine/LPS Stimulation

The action on liver injury by Galactosamine/LPS stimulation wasevaluated by elevation of blood alanine transaminase (ALT) amount as anindex. Galactosamine (700 mg/kg) and LPS (5 μg/kg) were administeredintraperitoneally to BALB/c mice (female, 7 weeks old, Japan CharlesRiver). After 8 hr, the blood was collected in the presence of heparin.The obtained blood was centrifuged (4° C., 10000×rpm, 10 min), and theblood plasma was collected, and the ALT amount in the blood plasma wasmeasured by 7180 type Hitachi automated analytical apparatus (HitachiHigh-Technologies Corporation). Compound 6 was dissolved in 10% captisolsolution (0.3, 1, 3 mg/kg), and the solution was administeredintravenously to the mice in the tail vein 1 hr before Galactosamine/LPSadministration. The mean±standard errors of the ALT amount in the bloodplasma of each group were shown in Table 4.

TABLE 4 Galactosamine/LPS stimulation Non-stimulation Compound No. 6(mg/kg) Vehicle Vehicle 0.3 1 3 ALT 83 ± 1021 ± 570 ± 361 ± 104 ± (IU/L)4 185### 94 60** 10*** Sample number = 5 (non-stimulation group) or 10(Galactosamine/LPS stimulation group), ###P < 0.001 vs.Non-stimulation/Vehicle group (Aspin-Welch t test), **P < 0.005, ***P <0.0005 vs. Galactosamine/LPS stimulation-Vehicle group (One-tailedShirley-Williams test)

As shown in Table 4, Compound 6 (0.3, 1, 3 mg/kg) dose-dependently andsignificantly inhibited the increase in the ALT amount in the bloodplasma due to Galactosamine/LPS stimulation. As is clear from theresults, it is suggested that Compound 6 has effect on the prophylaxisor treatment of liver injury.

Test Example 4 Inhibitory Effect on TNFα Production from HMGB-1Stimulated-Human Kupffer Cell

TLR4 signal inhibitory activity in human Kupffer cell was evaluated asan inhibition rate of the test compound for TNFα produced by addition ofHMGB-1 (SHINO-TEST), using human primary Kupffer cells (Cat# HUKCCS,Lot#HK8226) purchase from GIBCO. Cell suspension prepared in RPMI1640-Gluta MAXTM medium supplemented with 10% inactivated bovine fetalserum was plated in 96-well I-type collagen-coated plate so as tocontain 3.1×10⁴ cells/100 μL/well. Then, the cells were cultured for 6hr at 37° C. under 5% CO₂195% air to be adhered to the bottom of theplate. The non-adhered cells were rinsed off with PBS, and the testcompound dissolved in DMSO was added to the adhered cells (finalconcentration: 1, 10, 100 nM), and the mixture was cultured for 1 hr.Then, HMGB-1 was added thereto (final concentration: 10 μg/mL), and themixture was incubated for additional 24 hr. TNFα production amountcontained in the culture supernatant was quantified by ELISA method (R&Dsystems). TNFα production inhibition rate (%) was calculated using thevalue under the HMGB-1-free condition as control of 100% inhibition andthe value under the compound-free condition as control of 0% inhibition.The results are shown in Table 5.

TABLE 5 Compound TNFα production Compound concentration inhibition rateNo. (nM) (% inhibition) 6 1 45 10 82 100 85

Test Example 5 Evaluation of Analgesic Action on OxaliplatinInduced-Neuropathic Pain Model Mouse

Oxaliplatin was diluted with saline by the predetermined concentration,and administered intraperitoneally to mice (C57BL/6N, male, 8 weeks old)at 0.3 mg/kg. The test compound was dissolved in 10% captisol or 10%captisol containing 0.1% N-methyl-2-pyrrolidone. The compound wasadministered intravenously (0.1-10 mg/kg body weight) to the miceimmediately before intraperitoneal administration of various anticancerdrugs. The pain threshold was measured 1 week after oxaliplatinadministration. The pain threshold was evaluated as a weighted value(gram) showing pseudo-escape reaction, when the footpad of the righthind limb was pressed using balance type pressurizing device (UgoBasile). The results are shown in Table 6. The values in the table showthe mean±standard errors of the weighted values.

TABLE 6 Normal 322.0 ± 22.0 Vehicle  83.3 ± 23.0 Compound No. 6 1 mg/kg190.0 ± 46.1 3 mg/kg 153.3 ± 46.1 10 mg/kg  310.0 ± 45.6^(#) Normal273.3 ± 11.2 Vehicle 116.7 ± 20.3 Compound No. 14 0.1 mg/kg 208.0 ± 33.80.3 mg/kg 215.0 ± 21.6 1 mg/kg  310.0 ± 33.8^(#) Normal 323.3 ± 32.0Vehicle 121.7 ± 16.0 Compound No. 21 0.1 mg/kg 160.0 ± 29.7 0.3 mg/kg265.0 ± 58.5 1 mg/kg  285.0 ± 19.3^(#) Shirley-Williams^(#); P < 0.01 vsvehiclePharmaceutical Preparation Example 1 (Production of Capsule)

1) Compound of Example 1 30 mg 2) Finely powdered cellulose 10 mg 3)Lactose 19 mg 4) Magnesium stearate  1 mg Total 60 mg 1), 2), 3) and 4)are mixed, and packed into a gelatin capsule.1), 2), 3) and 4) are mixed, and packed into a gelatin capsule.Pharmaceutical Preparation Example 2 (Production of Tablets)

1) Compound of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4)Carboxymethylcellulose calcium 44 g 5) Magnesium stearate  1 g 1000tablets, total 140 g 

The total quantities of 1), 2) and 3) and 30 g of 4) are kneaded withwater, the kneaded mixture is then subjected to vacuum drying andgranulation. To said granular powder is admixed 14 g of 4) and 1 g of 5)and the mixture subjected to tableting using a tableting machine. Inthis way, 1000 tablets containing 30 mg of compound of Example 1 pertablet are obtained.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have TLR4 signaling inhibitoryaction and are useful as agents for the prevention and treatment ofautoimmune diseases and/or inflammatory diseases, or diseases such aschemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-inducedto neuropathic pain (CINP), liver injury, ischemia-reperfusion injury(IRI) and the like.

This application is based on patent application No. 2015-095817 filed onMay 8, 2015 in Japan, the contents of which are incorporated in fullherein.

The invention claimed is:
 1. Ethyl(2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.2. A pharmaceutical composition comprising the compound of claim 1, anda pharmacologically acceptable carrier.
 3. A method of inhibitingtoll-like receptor 4 in a mammal, which comprises administering aneffective amount of the compound of claim 1 to the mammal.